Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds

ABSTRACT

The compounds of formula I herein exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, for treating a patient suffering from, or subject to, a physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of InternationalApplication No. PCT/US99/12312, filed Jun. 3, 1999, which is, in turn, acontinuation-in-part of U.S. application Ser. No. 09/090,492, filed Jun.3, 1998, which is, in turn, a continuation-in-part of InternationalApplication No. PCT/US97/22406, filed Dec. 3, 1997, which is, in turn, acontinuation-in-part of U.S. Provisional Application No. 60/033,159,filed Dec. 13, 1996, now abandoned.

FIELD OF THE INVENTION

[0002] The compounds of formula I exhibit useful pharmacologicalactivity and accordingly are incorporated into pharmaceuticalcompositions and used in the treatment of patients suffering fromcertain medical disorders. More specifically, they are Factor Xainhibitors. The present invention is directed to compounds of formula I,compositions containing compounds of formula I and their use fortreating a patient suffering from, or subject to, conditions which canbe ameliorated by the administration of an inhibitor of Factor Xa.

[0003] Factor Xa is the penultimate enzyme in the coagulation cascade.Both free factor Xa and factor Xa assembled in the prothrombinasecomplex (Factor Xa, Factor Va, calcium and phospholipid) are inhibitedby compounds of formula I. Factor Xa inhibition is obtained by directcomplex formation between the inhibitor and the enzyme, and is thereforeindependent of the plasma co-factor antithrombin III. Effective factorXa inhibition is achieved by administering the compounds either by oraladministration, continuous intravenous infusion, bolus intravenousadministration or any other parenteral route such that it achieves thedesired effect of preventing the factor Xa induced formation of thrombinfrom prothrombin.

[0004] Anticoagulant therapy is indicated for the treatment andprophylaxis of a variety of thrombotic conditions of both the venous andarterial vasculature. In the arterial system, abnormal thrombusformation is primarily associated with arteries of the coronary,cerebral and peripheral vasculature. The diseases associated withthrombotic occlusion of these vessels principally include acutemyocardial infarction (AMI), unstable angina, thromboembolism, acutevessel closure associated with thrombolytic therapy and percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, and intermittent claudication and bypass grafting (CABG) of thecoronary or peripheral arteries. Chronic anticoagulant therapy may alsobe beneficial in preventing the vessel luminal narrowing (restenosis)that often occurs following PTCA and CABG, and in the maintenance ofvascular access patency in long-term hemodialysis patients. With respectto the venous vasculature, pathologic thrombus formation frequentlyoccurs in the veins of the lower extremities following abdominal, kneeand hip surgery (deep vein thrombosis, DVT). DVT further predisposes thepatient to a higher risk of pulmonary thromboembolism. A systemic,disseminated intravascular coagulopathy (DIC) commonly occurs in bothvascular systems during septic shock, certain viral infections andcancer. This condition is characterized by a rapid consumption ofcoagulation factors and their plasma inhibitors resulting in theformation of life-threatening clots throughout the microvasculature ofseveral organ systems. The indications discussed above include some, butnot all, of the possible clinical situations where anticoagulant therapyis warranted. Those experienced in this field are well aware of thecircumstances requiring either acute or chronic prophylacticanticoagulant therapy.

SUMMARY OF THE INVENTION

[0005] This invention is directed to compounds of formula I below aswell as to their pharmaceutical use for treating a patient sufferingfrom a physiological disorder capable of being modulated by inhibitingthe activity of Factor Xa:

[0006] wherein

[0007] is a monocyclic heteroaryl group containing at least one nitrogenatom, or a bicyclic heteroaryl group which includes a first proximalring that is attached to Z and a ring distal to said first ring, saiddistal ring including at least one nitrogen atom;

[0008] Z is alkylenyl, —(CH₂)_(r)C(O)NR″(CH₂)_(s)—,—(CH₂)_(s)R″NC(O)(CH₂)_(r)—, —(CH₂)_(r)NR″(CH₂)_(s)— or—(CH₂)_(s)NR″(CH₂)_(r)—;

[0009] R₁ is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, R′O(CH₂)_(x)—, R′O₂C(CH₂)_(x)—,R′C(O)(CH₂)_(x)—, Y¹Y²NC(O)(CH₂)_(x)—, or Y¹Y²N(CH₂)_(x)—;

[0010] R′ and R″ are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkenyl, optionally substitutedheteroaralkenyl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl;

[0011] R₂ is hydrogen, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, optionally substituted aralkenyl, optionallysubstituted heteroaralkenyl, R₃R₄NC(O)(CH₂)x—, R₃S(O)_(p)— orR₃R₄NS(O)_(p)—;

[0012] R₃ is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl, optionallysubstituted aralkenyl or optionally substituted heteroaralkenyl, or R₁and R₃ taken together with the —N—S(O)_(p)— moiety or the—N—S(O)_(p)—NR₄— moiety through which R₁ and R₃ are linked form a 5 to 7membered optionally substituted heterocyclyl; and

[0013] R₄ is hydrogen, optionally substituted alkyl, optionallysubstituted cycloalkyl or optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl, or R₃ and R₄ taken together with the nitrogento which R₃ and R₄ are attached form an optionally substituted 4 to 7membered heterocyclyl;

[0014] X₁ and X_(1a) are independently selected from H, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheteroaralkyl, or X₁ and X_(1a) taken together form oxo;

[0015] X₂ and X_(2a) are independently H, or taken together form oxo;

[0016] X₃ is H, hydroxy, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted aralkyl or optionally substituted heteroaralkyl, or X₃ andone of X₁ and X_(1a) taken together form a 4 to 7 membered cycloalkyl;

[0017] X₄ is H, optionally substituted alkyl, optionally substitutedaralkyl, or hydroxyalkyl;

[0018] X₅, X_(5a) and X_(5b) are independently selected from H R₅R₆N—,(hydroxy)HN—, (alkoxy)HN—,-or (amino)HN—, R₇O—, R₅R₆NCO—, R₅R₆NSO₂—,R₇CO—, halo, cyano, nitro and R₈(O)C(CH₂)_(q)—, and, when

[0019] is a bicyclic heteroaryl group, one of X₅, X_(5a) and X_(5b) is asubstituent that is alpha to a nitrogen of said distal ring of

[0020] and is selected from the group consisting of H, hydroxy and H₂N—,(optionally substituted lower alkyl)HN (hydroxy)HN—, (alkoxy)HN—, and(amino)HN—;

[0021] Y¹ and Y² are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl or optionally substituted heteroaralkyl,or Y¹ and Y² taken together with the N through which Y¹ and Y² arelinked form a 4 to 7 membered heterocyclyl;

[0022] R₅ and R₆ are independently H or optionally substituted loweralkyl, or one of R₅ and R₆ is H and the other of R₅ and R₆ is R₈(O)CCH₂—or lower acyl;

[0023] R₇ is H, optionally substituted lower alkyl, lower acyl orR₈(O)CCH₂—;

[0024] R₈ is H, optionally substituted lower alkyl, alkoxy or hydroxy;

[0025] m is 0, 1, 2 or3;

[0026] p and r are independently 1 or 2;

[0027] q is 0 or 1,

[0028] s is 0, 1 or 2; and

[0029] x is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable saltthereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0030] As used above, and throughout the description of the invention,the following terms, unless otherwise indicated, shall be understood tohave the following meanings:

[0031] Definitions

[0032] “Patient” includes both humans and other mammals.

[0033] “Alkyl” means an aliphatic hydrocarbon group which may bestraight- or branched-chain having about 1 to about 20 carbon atoms inthe chain. Preferred alkyl groups have 1 to about 12 carbon atoms in thechain. Branched means that one or more lower alkyl groups such asmethyl, ethyl or propyl are attached to a linear alkyl chain. “Loweralkyl” means an alkyl group having about 1 to about 4 carbon atoms inthe chain which may be straight or branched. The alkyl group may besubstituted with one or more “alkyl group substituents” which may be thesame or different, and include halo, cycloalkyl, hydroxy, alkoxy,aryloxy, heteroaryloxy, amino, acylamino, aroylamino, carboxy,alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl orR₉R₁₀NCO—, wherein R₉ and R₁₀ are independently hydrogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedaralkyl or optionally substituted heteroaralkyl, or R₉ and R₁₀ takentogether with the N through which R₉ and R₁₀ are linked form a 4 to 7membered heterocyclyl. Exemplary alkyl groups include methyl,trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl,carboxymethyl, methoxycarbonylethyl, benzyloxycarbonylmethyl,pyridylmethyloxycarbonylmethyl.

[0034] “Alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkenyl groupshave about 2 to about 12 carbon atoms in the chain, more preferablyabout 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower allyl groups such as methyl, ethyl or propyl are attached toa linear alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain, which may be straight or branched. The alkenyl groupmay be substituted by one or more halo or cycloalkyl groups. Exemplaryalkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl,3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl anddecenyl.

[0035] “Cycloalkyl” means a non-aromatic mono- or multicyclic ringsystem of about 3 to about 10 carbon atoms. Exemplary monocycliccycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl andcycloheptyl. The cycloalkyl group is optionally partially unsaturated oroptionally substituted by one or more halo, methylene (H₂C═), alkyl,fused aryl or fused heteroaryl. Exemplary multicyclic cycloalkyl ringsinclude 1-decalin, adamant-(1- or 2-)yl and norbornyl.

[0036] “Heterocyclyl” means a non-aromatic monocyclic or multicyclichydrocarbon ring system of about 3 to about 10 ring atoms in which oneor more of the carbon atoms of the ring systems is replaced by anelement other than carbon. Preferred rings include about 5 to about 6ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur.The heterocyclyl is optionally partially unsaturated or optionallysubstituted by one or more alkyl, halo, aryl, heteroaryl, fused aryl orfused heteroaryl. Exemplary monocyclic heterocyclyl ring systems includepyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl andtetrahydrothiopyranyl. The thio or nitrogen moiety of the heterocyclylmay also be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Exemplary multicyclic heterocyclyl ring systems include 1,4diazabicyclo-[2.2.2]octane and 1,2-cyclohexanedicarboxylic acidanhydride.

[0037] “Aryl” means a 6 to 10 membered aromatic monocyclic ormulticyclic hydrocarbon ring system. Exemplary aryl include phenyl ornaphthyl, either of which may be substituted with one or more ringsystem substituents which may be the same or different, where “ringsystem substituents” are as defined herein.

[0038] “Ring system substituents” means substituents attached to anaromatic or non-aromatic ring system, inclusive of hydrogen, alkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino,aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkykthio, fused cycloalkyl, fusedheterocyclyl, arylazo, heteroarylazo, R₉R₁₀N—, R₉R₁₀NCO— or R₉R₁₀NSO₂—,wherein R₉ and R₁₀ are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted aralkyl oroptionally substituted heteroaralkyl, or R₉ and R₁₀ taken together withthe N through which R₉ and R₁₀ are linked form a 4 to 7 memberedheterocyclyl. When a ring system is saturated or partially saturated the“ring system substituents” further include methylene (CH₂═), oxo (O═) orthio (S═). Preferred ring system substituents include hydrogen, alkyl,hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy, cyano,alkoxycarbonyl, acylamino, alkylthio, R₉R₁₀N—, R₉R₁₀NCO— and R₉R₁₀NSO₂—,where R₉ and R₁₀ are independently optionally substituted alkyl, aryl,aralkyl or heteroaralkyl. Particularly, preferred phenyl groupsubstituents are hydroxy, halogen, alkyl and amino.

[0039] “Heteroaryl” means about a 5- to about a 10-membered aromaticmonocyclic or multicyclic hydrocarbon ring system in which one or moreof the carbon atoms in the ring system is replaced by an element otherthan carbon, for example nitrogen, oxygen or sulfur. A nitrogen atom inthe ring system may be optionally oxidized to the N-oxide. Where theheteroaryl is a multicyclic hydrocarbon ring system then one of saidring systems is optionally partially or fully saturated. The“heteroaryl” may also be substituted by one or more of theabove-mentioned “ring system substituents”. Exemplary heteroaryl groupsinclude pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl,isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,imidazo[2,1-b]thiazolyl, thiono[3,2-b]pyridyl, thieno[2,3-b]pyridyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl and1,2,3,4tetrahydroisoquinolinyl. Where the heteroaryl is a multicyclichydrocarbon ring system then it may be bonded to the rest of themolecule through any atom of the ring system thereof capable of such.Preferred heteroaryl groups in the R₁ substituent include benzothienyl,thienyl, thienopyridyl, isoquinolinyl and quinolinyl all of which may beoptionally substituted. Preferred

[0040] bicyclic heteroaryl groups include isoquinolinyl, quinolinyl,benzothienyl, isoquinolinyl, isoquinazolinyl, thienopyridyl,quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1,2- or 2,3-)benzodiazinyl and imidazopyridyl. Preferred

[0041] monocyclic heteroaryl groups include pyridyl. Preferredheteroaryl groups in the R₃ substituent of formula I includebenzothienyl, thieno[3,2-b]pyridyl, naphthyl, and thieno[2,3-b]pyridyl.

[0042] “Aralkyl” means an aryl-alkyl-group in which the aryl and alkylare as previously described. Preferred aralkyls contain a lower alkylmoiety. Exemplary aralkyl groups include benzyl, 2-phenethyl andnaphthalenemethyl.

[0043] “Heteroaralkyl” means a heteroaryl-alkyl-group in which theheteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl moiety. Exemplary heteroaralkylgroups include thienylalkyl, pyridylalkyl, imidazolylalkyl,pyrazinylalkyl, benzimidazolylmethyl, indolylmethyl, pyrazolylmethyl,and thiazolylmethyl.

[0044] “Aralkenyl” means an aryl-alkenyl-group in which the aryl andalkenyl are as previously described. Preferred aralkenyls contain alower alkenyl moiety. An exemplary aralkenyl group is 2-phenethenyl.

[0045] “Heteroaralkenyl” means a heteroaryl-alkenyl-group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl moiety. Exemplaryheteroaralkenyl groups include thienylallyl, thienyl-2-ethenyl,pyridyl-2-ethenyl, imidazolyl-2-ethenyl and pyrazinyl-2-ethenyl,thienylpropenyl, pyridylpropenyl, imidazolylpropenyl andpyrazinyl-propenyl.

[0046] “Hydroxyalkyl” means an HO-alkyl-group in which alkyl is aspreviously defined. Preferred hydroxyalkyls contain lower alkyl.Exemplary hydroxyalkyl groups include hydroxymethyl and 1-hydroxyethyl.

[0047] “Acyl” means an H—CO— or alkyl-CO-group in which the alkyl groupis as previously described. Preferred acyls contain a lower alkyl.Exemplary acyl groups include formyl, acetyl, propanoyl,2-methylpropanoyl, butanoyl and palmitoyl.

[0048] “Aroyl” means an aryl-CO-group in which the aryl group is aspreviously described. Exemplary aroyl groups include benzoyl and 1- and2-naphthoyl.

[0049] “Alkoxy” means an alkyl-O-group in which the alkyl group is aspreviously described. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, heptoxy and t-butoxy.

[0050] “Aryloxy” means an aryl-O-group in which the aryl group is aspreviously described. Exemplary aryloxy groups include phenoxy andnaphthoxy.

[0051] “Heteroaryloxy” means an heteroaryl-O-group in which theheteroaryl group is as previously described. Exemplary heteroaryloxygroups include thienyloxy.

[0052] “Aralkyloxy” means an aralkyl-O-group in which the aralkyl groupsis as previously described. Exemplary aralkyloxy groups includebenzyloxy and 1- or 2-naphthylmethoxy.

[0053] “Alkylthio” means an alkyl-S-group in which the alkyl group is aspreviously described. Exemplary alkylthio groups include methylthio,ethylthio, i-propylthio and heptylthio.

[0054] “Arylthio” means an aryl-S-group in which the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

[0055] “Aralkylthio” means an aralkyl-S-group in which the aralkyl groupis as previously described. An exemplary aralkylthio group isbenzylthio.

[0056] “R₉R₁₀N—” means a substituted or unsubstituted amino group,wherein R₉ and R₁₀ are as previously described. Exemplary amino groupsinclude amino (H₂N—), methylamino, ethylmethylamino, dimethylamino,diethylamino, pyrrolidino and piperidino.

[0057] “Alkoxycarbonyl” means an alkyl-O—CO-group wherein alkyl is asdefined herein. Exemplary alkoxycarbonyl groups include (methoxy-,ethoxy- and t-butoxy)carbonyl.

[0058] “Aryloxycarbonyl” means an aryl-O—CO-group wherein aryl is asdefined herein. Exemplary aryloxycarbonyl groups include phenoxy- andnaphthoxycarbonyl.

[0059] “Aralkoxycarbonyl” means an aralkyl-O—CO-group wherein aralkyl isas defined herein. An exemplary aralkoxycarbonyl group isbenzyloxycarbonyl.

[0060] “R₉R₁₀NCO—” means a substituted or unsubstituted carbamoyl group,wherein R₉ and R₁₀ are as previously described. Exemplary carbamoylgroups are carbamoyl (H₂NCO—) and dimethylcarbamoyl (Me₂NCO—).

[0061] “R₉R₁₀NSO₂—” means a substituted or unsubstituted sulfamoylgroup, wherein R₉ and R₁₀ are as previously described. Exemplarysulfamoyl groups are sulfamoyl (H₂NSO₂—) and dimethylsulfamoyl(Me₂NSO₂—).

[0062] “Acylamino” is an acyl-NH-group wherein acyl is as definedherein.

[0063] “Aroylamino” is an aroyl-NH-group wherein aroyl is as definedherein.

[0064] “Alkylsulfonyl” means an alkyl-SO₂-group wherein alkyl is asdefined herein. Preferred groups are those in which the alkyl group islower alkyl.

[0065] “Arylsulfonyl” means an aryl-SO₂-group wherein aryl is as definedherein.

[0066] “Alkylenyl” means, for example, a methylenyl, ethylenyl orpropylenyl group.

[0067] “Halo” means fluoro, chloro, bromo, or iodo. Preferred arefluoro, chloro or bromo, and more preferred are fluoro or chloro.

[0068] Preferred Embodiments

[0069] A preferred embodiment of the invention is a method for treatinga patient suffering from a physiological disorder capable of beingmodulated by inhibiting an activity of Factor Xa by administering atherapeutically effective amount of a compound of formula I.

[0070] A preferred compound aspect of the invention is the compound offormula I wherein R₁ is H, optionally substituted heteroaralkyl,optionally substituted alkenyl, optionally substituted aralkyl oroptionally substituted alkyl.

[0071] Another preferred compound aspect of the invention is thecompound of formula I wherein R₂ is R₃S(O)_(p)—, and more preferable isR₃S(O)_(p)— wherein p is 2.

[0072] Another preferred compound aspect of the invention is thecompound of formula I wherein R₂ is hydrogen, optionally substitutedaralkyl, optionally substituted heteroaralkyl, optionally substitutedaralkenyl, optionally substituted heteroaralkenyl, or R₃R₄NC(O)(CH₂)x—.Another preferred compound aspect of the invention is the compound offormula I wherein R₃ is hydrogen, optionally substituted phenyl,optionally substituted naphthyl, optionally substituted thienyl,optionally substituted benzothienyl, optionally substitutedthienopyridyl, optionally substituted quinolinyl, or optionallysubstituted isoquinolinyl; more preferred R₃ is optionally selected fromsubstituted naphthyl, optionally substituted thienyl, optionallysubstituted benzothienyl and optionally substituted thienopyridyl.

[0073] Another preferred compound aspect of the invention is thecompound of formula I wherein R₂ is selected from the group consistingof

[0074] Another preferred compound aspect of the invention is thecompound of formula I wherein R₂ is selected from the group consistingof

[0075] Another preferred compound aspect of the invention is thecompound of formula I wherein R₂ is

[0076] R_(a) is hydrogen, alkyl, hydroxy, alkoxy, Y¹Y²N—, halogen,—CO₂R_(d), —C(O)NY¹Y², —(CH₂)_(x)OR_(d), —(CH₂)_(x)NY¹Y², or —CN;

[0077] R_(b) and R_(c) are independently selected from hydrogen,hydroxy, alkoxy, Y¹Y²N—, halogen, —CO₂R_(d), —C(O)NY¹Y²,—(CH₂)_(x)OR_(d), —(CH₂)_(x)NY¹Y², —CN, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl, optionally substituted heteroaralkyl,optionally substituted aralkenyl or optionally substitutedheteroaralkenyl, or R_(b) and R_(c) taken together with the carbon atomsthrough which they are linked form an optionally substituted 5 to 7membered fused cycloalkyl, or an optionally substituted 5 to 7 memberedfused heterocyclyl ring or an optionally substituted 6 membered fusedaryl, or an optionally substituted 5 to 6 membered fused heteroarylring;

[0078] R_(d) is hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl or optionally substituted heteroaralkyl;

[0079] Y¹ and Y² are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted aralkyl oroptionally substituted heteroaralkyl, or Y¹ and Y² taken together withthe N through which Y¹ and Y² are linked form a 4 to 7 memberedheterocyclyl;

[0080] Z₁ is S or —CH═CH—; and

[0081] x is 1, 2, 3, 4, or 5.

[0082] Another preferred compound aspect of the invention is thecompound of formula I wherein R₃ is optionally substituted aralkenyl oroptionally substituted heteroaralkenyl, more preferably optionallysubstituted heteroaralkenyl.

[0083] Another preferred compound aspect of the invention is thecompound of formula I wherein when R₃ is optionally substituted arkey oroptionally substituted heteroaralkenyl, then the alkenyl moiety thereofis of the formula

[0084] Another preferred compound aspect of the invention is thecompound of formula I wherein when R₃ is optionally substitutedaralkenyl or optionally substituted heteroaralkenyl, then the alkenylmoiety thereof is of the formula

[0085] wherein one of Q₁ and Q₂ is hydrogen, lower alkyl (morepreferably methyl), or halo (more preferably fluoro or chloro) and theother of Q₁ and Q₂ is lower alkyl (more preferably methyl), or halo(more preferably fluoro or chloro).

[0086] Another preferred compound aspect of the invention is thecompound of formula I wherein when R₃ is optionally substitutedaralkenyl then the aryl moiety thereof is halo substituted phenyl; morepreferably chloro substituted phenyl.

[0087] Another preferred compound aspect of the invention is thecompound of formula I wherein when R₃ is optionally substitutedheteroaralkenyl then the heteroaryl moiety thereof is halo substitutedthienyl, more preferably 2-chlorothien-5-yl.

[0088] Another preferred compound aspect of the invention is thecompound of formula I wherein Z is methylenyl.

[0089] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0090] is selected from the group consisting of

[0091] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0092] is selected from the group consisting of

[0093] Another preferred compound aspect of the invention is thecompound of formula I wherein Z₁ is —CH═CH—; and R_(b) and R_(c) takentogether with the carbon atoms through which R_(b) and R_(c) are linkedform an optionally substituted 5 or 6 membered heteroaryl ring,preferably containing at least one hetero atom which is preferably N, oran optionally substituted 6 membered aryl ring, and wherein saidoptional substituents are preferably selected from chloro, hydroxy andamino.

[0094] Another preferred compound aspect of the invention is thecompound of formula I wherein Z₁ is —CH═CH—; R_(b) is hydrogen; andR_(c) is an optionally substituted heteroaryl ring, preferably 5 or 6membered heteroaryl ring, more preferably containing at least one heteroatom which is preferably N or S, or an optionally substituted 6 memberedaryl ring, and wherein said optional substituents are preferably chloro,hydroxy or amino.

[0095] Another preferred compound aspect of the invention is thecompound of formula I wherein Z₁ is S (sulfur).

[0096] Another preferred compound aspect of the invention is thecompound of formula I wherein Z₁ is S (sulfur); and R_(b) and R_(c)taken together with the carbon atoms through which R_(b) and R_(c) arelinked form an optionally substituted 5 or 6 membered heteroaryl ring,preferably containing at least one hetero atom which is preferably N, oran optionally substituted 6 membered aryl ring, and wherein saidoptional substituents are preferably chloro, hydroxy or amino.

[0097] Another preferred compound aspect of the invention is thecompound of formula I wherein Z₁ is S (sulfur); R_(b) is hydrogen; andR_(c) is an optionally substituted heteroaryl ring, preferably a 5 or 6membered heteroaryl ring, preferably containing at least one hetero atomwhich is preferably N or S, or an optionally substituted 6 membered arylring, and wherein said optional substituents are preferably chloro,hydroxy or amino.

[0098] Another preferred compound aspect of the invention is thecompound of formula I wherein Z is methylenyl, and m is 1.

[0099] Another preferred compound aspect of the invention is thecompound of formula I wherein X₂ and X_(2a) taken together are oxo.

[0100] Another preferred compound aspect of the invention is thecompound of formula I wherein each of X₁, X_(1a), X₃ and X₄ is H.

[0101] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0102] is an optionally substituted isoquinolinyl; more preferred theisoquinolinyl is attached to Z at the 7-position thereof.

[0103] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0104] is an optionally substituted quinolinyl; more preferred thequinolinyl is attached to Z at the 7-position thereof.

[0105] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0106] is an optionally substituted quinazolinyl; more preferred thequinazolinyl is attached to Z at the 7-position thereof.

[0107] Another preferred compound aspect of the invention is thecompound of formula I wherein

[0108] is an optionally substituted moiety of formula

[0109] and W is S, O or NR₁₁, wherein R₁₁ is H, alkyl, aralkyl,heteroaralkyl, or R₈(O)C(CH₂)_(q)—, and A is independently CH or N; morepreferably the moiety is bonded to Z through the ring containing W, andyet more preferably the moiety is bonded to Z through the ringcontaining W at the 2-position thereof.

[0110] Another preferred compound aspect of the invention is thecompound of formula I wherein one of X₅, X_(5a) and X_(5b) is H, hydroxyor amino, more preferably hydroxy or amino substituted on the proximalring of

[0111] at a position that is adjacent to the position of the proximalring to which Z is attached.

[0112] Another preferred compound aspect of the invention is thecompound of formula I wherein one of X₅, X_(5a) and X_(5b) is asubstituent on the distal ring of

[0113] at the position alpha to a nitrogen thereof selected from H,H₂N—, (optionally substituted loweralkyl)HN—, (hydroxy)HN—, and(amino)HN—.

[0114] Preferred species according to the invention are selected fromthe group consisting of:

[0115]3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-1H-indol-2-ylmethyl)amino]propionicacid methyl ester;

[0116]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(3-ethylbutyl)amino]pyrrolidin-2-one;

[0117]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[benzyl-(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0118]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)thiazol-5-ylmethylamino]pyrrolidin-2-one;

[0119]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;

[0120]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-ylmethyl)amino]pyrrolidin-2-one;

[0121]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorothieno[2,3-b]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[0122]1-(4-Aminoquinazolin-7-ylmethyl)3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[0123]3-{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-ylamino]methyl}-1H-quinolin-2-one;

[0124]1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0125] 2-(5-Chlorothiophen-2-yl)-ethenesulfonic acid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)yl]amide;

[0126]{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amino}aceticacid isopropyl ester;

[0127]1-(4-Aminoquinolin-7-ylmethyl)3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0128] 5-Chloro-1H-benzoimidazole-2-sulfonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide;

[0129] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate;

[0130] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidehydrochloride;

[0131] 7-Methoxynaphthalene-2-sulfonic acid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0132] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0133] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-hydroxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]amide;

[0134] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]methylamidetrifluoroacetate;

[0135] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;

[0136] Benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0137] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0138] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidehydrochloride;

[0139] 7-Methoxynaphthalene-2-sulfonicacid[1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxo pyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0140] 4-(2-Chloro-6-nitophenoxy)benzene sulfonicacid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0141] 7-Methoxynaphthalene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0142] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxo pyrrolidin-3-(S)-yl]amide trifluoroacetate;

[0143] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0144] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0145] Benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0146] 7 Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;

[0147] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide;

[0148] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5ylmethyl)-2-oxopyolidin-3-(S)-yl]amidetrifluoroacetate;

[0149] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;

[0150] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide;

[0151] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-6-ylmethyl)2-oxopyrrolidin-3-(S)-yl]amide;

[0152] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;

[0153] 7-Methoxynaphthalene-2-sulfonicacid[1-(1H-benzimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0154] 7-Methoxynaphthalene-2-sulfonicacid[2-(1H-benzimidazol-5-ylethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0155] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminoquinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamidetrifluoroacetate,

[0156] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0157] 7-Methoxynaphthalene-2-sulfonicacid[2-(6-aminothieno[2,3-d]pyrimidin-6yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0158] 7-Methoxynaphthalene-2-sulfonicacid[1-(7-aminothieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate,

[0159] 7-Methoxynaphthalene-2-sulfonicacid[1-(7-hydroxythieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0160] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate;

[0161] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-hydroxythieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate;

[0162] Benzo[b]thiophene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate;

[0163] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0164] Thieno[2,3-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0165] 4-Pyridin-3-yl-thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0166] 5′Chloro-[2,2′]bithiophenyl-5-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;

[0167] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;

[0168] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0169] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0170] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0171] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0172] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0173] 5′-Chloro-[2,2′]bithiophenyl-5-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0174] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0175] 2(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0176] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0177] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;

[0178] 3(R)-5 Chlorothiophen-2-yl)-ethenesulphonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0179]2-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-chloro-benzo[b]thiophene-2-sulfonyl)-amino]-aceticacid methyl ester, trifluoroacetate;

[0180] 2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate;

[0181] 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate;

[0182] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-quinolin-6-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide,ditrifluoroacetate:

[0183]N-(3-Amino-pyridin-4-yl)2-[3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-acetamide;

[0184]2-[3-(7-Methoxy-naphthalene-2-sulfonylamino)2-oxo-pyrrolidin-1-yl]-N-pyridin-4-yl-acetamide;

[0185] 6-Chlorobenzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate;

[0186] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;

[0187] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonicacid{2-oxo1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoacetate;

[0188] Thieno[3,2-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)ethyl]-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0189] 2(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;

[0190] (S)-5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0191] (S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0192]((6-Chloro-benzo[b]thiophene-2-sulfonyl){-2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester,

[0193]((6-Chloro-benzo[b]thiophene-2-sulfonyl){-2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate;

[0194] 6-Chloro-benzo[b]thiophene-2-sulfonic acidallyl-{2-oxo-1-[2-(pyridin-4ylamino)ethyl]-pyrrolidin-3-yl}-amide;

[0195] 6-Chloro-benzo[b]thiophene-2-sulfonic acidmethyl-{2-oxo-1-[2pyridin-4-ylamino)ethyl]-pyrrolidin-3-yl}-amide;

[0196] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{1-[2-(-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amidetrifluoroacetate;

[0197] (S)- Thieno[3,2-b]pyridine-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0198]([5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid methyl ester;

[0199]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid isopropyl ester;

[0200]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate;

[0201] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoroacetate;

[0202]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid ethyl ester trifluoroacetate;

[0203]3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-acrylamidetrifluoroacetate;

[0204]1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chlorophenyl)ureatrifluoroacetate;

[0205]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5-chlorothiophen-2-yloxy)acetamidetrifluoroacetate;

[0206]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0207]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]3-(5-chlorothiophen-2-yl)ureatrifluoroacetate;

[0208] 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0209]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amino}aceticacid methyl ester trifluoroacetate;

[0210] 6-Chlorobenzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0211] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0212]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0213] 1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylamino]pyrrolidin-2-onetrifluoroacetate;

[0214]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate;

[0215]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0216]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-chlorothiophen-2-yl)ethenesulfonyl]amino}aceticacid methyl ester trifluoroacetate;

[0217]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;

[0218]{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chlorothiophen-2-yl)allyl]amino}aceticacid methyl ester trifluoroacetate;

[0219]{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)ureido}aceticacid methyl ester trifluoroacetate;

[0220]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate;

[0221]1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0222]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)ureatrifluoroacetate and 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0223]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;

[0224]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0225] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0226] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)-yl]-amide;

[0227] 7-Methoxy-naphthalene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0228] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0229] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0230] 5-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0231] Thieno[3,2-b]pyridine-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0232] 6-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0233] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0234] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(S)[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0235] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0236] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0237] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[(S)1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0238] Thieno[3,2-b]pyridine-2-sulfonicacid[(S)1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0239] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0240] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0241] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S))-yl]-amidetrifluoroacetate; and

[0242] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide.

[0243] More preferred species according to the invention are selectedfrom the group consisting of

[0244]3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-1H-indol-2-ylmethyl)amino]propionicacid methyl ester,

[0245]1-(4Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)(3-ethylbutyl)amino]pyrrolidin-2-one;

[0246]1(4-Aminoquinolin-7-ylmethyl)-3-(R)-[benzyI-(5-chloro1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0247]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)thiazol-5-ylmethylamino]pyrrolidin-2-one;

[0248]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;

[0249]1-(4-Aminoquinazolin-7-ylmethyl)3-(S)-[(6-chlorobenzo[b]thiophen-2-ylmethyl)amino]pyrrolidin-2-one;

[0250]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorothieno[2,3-b]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[0251]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[0252]3-{[1-(4-Aminoquinazolin-7-ylmethyl;2-oxopyrrolidin-3-(S)-ylamino]methyl}-1H-quinolin-2-one;

[0253]1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0254] 2-(5-Chlorothiophen-2-yl)ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amide;

[0255]{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amino}aceticacid isopropyl ester;

[0256]1-(4Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[0257] 5-Chloro-1H-benzoimidazole-2-sulfonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide;

[0258] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0259] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0260] 7-Methoxynaphthalene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamidetrifluoroacetate;

[0261] Benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0262] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0263] 7-Methoxynaphthalene-2-sulfonicacid-[1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0264] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0265] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0266] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0267] Benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0268] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-2-ylmethyl)-2-oxo-3-yl]amidetrifluoroacetate;

[0269] Benzo[b]thiophene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-2-ylmethyl)-2-oxo-3-yl]-amidetrifluoroacetate;

[0270] 5-Pyridin4-yl-thiophene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0271] 5-Pyridin-3-yl-thiophene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0272] Benzothiophene-2-sulfonicacid[1-(4-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0273] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;

[0274] 7Methoxynaphthalene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0275] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0276] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;

[0277] Thieno[3,2-b]pyridine-2-sulfonic acid[2-oxo-1-(1H-pyrrolo[2,3-cpyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide ditrifluoroacetate;

[0278] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;

[0279] 5′Chloro-[2,2′]bithiophenyl-5-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;

[0280] 6-Chlor-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0281] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0282] 5′-Chloro-[2,2′]bithiophenyl-5-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0283] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0284] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0285] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;

[0286] 2(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(S)-yl]-amide;

[0287] 3-(R)-5 Chlorothiophen-2-yl)-ethenesulphonic acid 81-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0288]2-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-chloro-benzo[b]thiophene-2-sulfonyl)-amino]-aceticacid methyl ester, trifluoroacetate;

[0289] 2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate;

[0290] 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl amide,trifluoroacetate;

[0291] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-quinolin-6-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide,ditrifluoroacetate;

[0292]N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-acetamide;

[0293]2-[3-(7-Methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-N-pyridin4-yl-acetamide;

[0294] 6-Chlorobenzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate;

[0295] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}amide;

[0296] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoacetate;

[0297] Thieno[3,2-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin4-ylamino)-ethyl]-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0298] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;

[0299] (S)-5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{-1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0300] (S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0301]((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester;

[0302]((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate;

[0303] 6-Chloro-benzo[b]thiophene-2-sulfonic acidallyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;

[0304] 6-Chloro-benzo[b]thiophene-2-sulfonic acidmethyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;

[0305] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amidetrifluoroacetate;

[0306] (S)-Thieno[3,2-b]pyridine-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;

[0307]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid methyl ester;

[0308]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid isopropyl ester;

[0309] ([2(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate;

[0310] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoroacetate;

[0311]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin4ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid ethyl ester trifluoroacetate;

[0312]3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-acrylamidetrifluoroacetate;

[0313]1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4chlorophenyl)ureatrifluoroacetate;

[0314]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5-chlorothiophen-2-yloxy)acetamidetrifluoroacetate;

[0315]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0316]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)ureatrifluoroacetate;

[0317] 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;

[0318]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amino}aceticacid methyl ester trifluoroacetate;

[0319] 6 -Chlorobenzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0320] Thieno[3,2-b]pyridine-2-sulfonicacid[l-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0321]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0322]1-(4Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylamino]pyrrolidin-2-onetrifluoroacetate;

[0323] N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate;

[0324]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0325] {[1-(4-Aminoquinazolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl][2-(5-chlorothiophen-2-yl)ethenesulfonyl]amino}aceticacid methyl ester trifluoroacetate;

[0326]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;

[0327]{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chlorothiophen-2-yl)allyl]amino}aceticacid methyl ester trifluoroacetate;

[0328]{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)ureido}aceticacid methyl ester trifluoroacetate;

[0329]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate;

[0330]1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0331]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)ureatrifluoroacetate;

[0332] 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0333]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;

[0334]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0335] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0336] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)-yl]-amide;

[0337] 7-Methoxy-naphthalene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0338] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0339] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0340] 5-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0341] Thieno[3,2-b]pyridine-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0342] Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0343] 5′-Chloro [2,2′]bithiophenyl-5-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0344] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0345] Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0346] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0347] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0348] Thieno[3,2-b]pyridine-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0349] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0350] 5′Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0351] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; and

[0352] 6Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide.

[0353] Still more preferred species according to the invention areselected from the group consisting of:

[0354] 7-Methoxynaphthalene-2-sulfonicacid[1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0355]1(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;

[0356] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;

[0357] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0358] 2-(5Chloro-thiophen-2-yl)-ethenesulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate;

[0359] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;

[0360] 6-Chlorobenzo[b]thiophene-2-sulfonic acid(2-oxo-1-[2-(pyridin4yl-amino)ethyl]-pyrrolidin-3-(S)-y}-amidetrifluoroacetate;

[0361]((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester;

[0362] Thieno[3,2-b]pyridine-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amideditrifluoroacetate;

[0363] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0364] 2(S)-(5Chloro-thiophen2-yl)-ethenesulfonicacid[1-(4amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate;

[0365] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide bistrifluoroacetate;

[0366] 6-Chlorobenzo[b]thiophene-2-sulfonic acid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-3(R)-pyrrolidin-3-yl]amide trifluoroacetate; and

[0367] 2-(5-Chlorothiophen-2-yl)-ethenesulfonicacid[1-(4-aminoquinazolin-7-yl methyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate.

[0368] This invention also encompasses all combinations of preferredaspects of the invention noted herein.

[0369] A compound of formula I may be prepared by the application oradaptation of known methods, by which is meant methods used heretoforeor described in the literature.

[0370] A preparative embodiment according to the invention for preparinga compound of formula I wherein Ar₁, R₁, R₂, X₃, X₄, X₅, X_(5a), X_(5b),Z and m are as defined above, X₁ and X_(1a) are H and X₂ and X_(2a),taken together, form oxo, may be prepared by coupling a compound offormula II

[0371] wherein X₃, X₄ and m are as defined above, X₁ and X_(1a) are H,X₂ and X_(2a) taken together form oxo, and P₁ is an (alkyl, aralkyl oraryl) carbamate with a compound of formula III

[0372] wherein Ar₁ is bicyclic heteroaryl, X₅, X_(5a), X_(5b) and Z areas defined above, and one of X₅, X_(5a), X_(5b) is H, chloro, bromo oraryloxy at the position alpha to the nitrogen of the distal ring of Ar₁,and L is a leaving group such as chloro, bromo, iodo, or optionallysubstituted lower alkylsulfonyloxy or arylsulfonyloxy, to give acompound of formula IV

[0373] A compound of formula IV is converted to a compound of formula Iby the methods herein described.

[0374] A compound of formula III may be prepared by reacting a compoundof formula V,

[0375] wherein X_(5c) is H, R₅R₆N—, R₇O—, R₅R₆NCO—, R₅R₆NSO₂—, R₇CO—,halo, cyano, nitro or R₈(O)C(CH₂)_(q)—, and wherein an amino or hydroxygroup thereof is suitably protected by an amino or hydroxy protectinggroup, n is 0 to 2, and Ar₂ is a monocyclic aryl or heteroaryl ring,with an appropriate malonic acid in a polar solvent such as pyridine orethanol and a base such as piperidine or pyridine at reflux to give acompound of formula VI

[0376] wherein R₁₂ is H, X_(5c) attached to the carboxymethylidenemoiety is H, X_(5c) attached to

[0377] n and

[0378] are as described above. Alternatively, a compound of formula Vmay be reacted with a suitable Wittig reagent in an inert solvent suchas THF to give a compound of formula VI wherein R₁₂ is lower alkyl,

[0379] X_(5c) attached to the carboxymethylidene moiety or

[0380] are as described above. When R₁₂ is lower alkyl, the ester ishydrolyzed to the corresponding carboxylic acid, wherein R₁₂ is H, by anappropriate strong acid or alkali base. The corresponding acid isconverted to the acid chloride using standard methods such as thionylchloride or is converted to the mixed anhydride in a polar solvent suchas acetone or THF to form an activated acyl compound. The activated acylcompound is then treated with a solution of NaN₃ in water at about −10°C. to about 25° C. to yield the corresponding acyl azide. The acyl azidecompound is then heated slowly in an inert solvent such as benzene ortoluene at about 60° C. to about 110° C. then concentrated in vacuo andheated in a higher boiling inert solvent such as 1,2-dichlorobenzene orphenyl ether at about 180° C. to about 240° C. with a catalyst such asiodine or tributylamine to obtain a compound of formula VII,

[0381] wherein X_(5c) is H, R₅R₆N—, R₇O—, R₅R₆NCO—, R₅R₆NSO₂—, R₇CO—,halo, cyano, nitro or R₈(O)C(CH₂)_(q)—, and wherein an amino or hydroxygroup thereof are suitably protected by an amino or hydroxy protectinggroup, n is 0, 1 or 2, and Ar₂ is a monocyclic aryl or heteroaryl ring.Alternatively the acyl azide compound can be added directly to a highboiling inert solvent such as phenyl ether at about 190° C. to about240° C. with a catalyst such as iodine or tributylamine to obtain thecompound of formula VII.

[0382] A compound of formula VIII,

[0383] prepared as described in Syn., 739 (1975) which is incorporatedherein by reference, wherein X_(5c) is H, R₅R₆N—, R₇O—, R₅R₆NCO—,R₅R₆NSO₂—, R₇CO—, halo, cyano, nitro or R₈(O)C(CH₂)_(q)—, and wherein anamino or hydroxy group thereof are suitably protected by an amino orhydroxy protecting group, n is 0, 1, or 2, and Ar₂ is a monocyclic arylor heteroaryl ring, or formula VII above, or those compounds wherein theamino or hydroxy moieties thereof are suitably protected by an amino orhydroxy protecting group, may be chlorinated using standard methods suchas POCl₃ or POCl₃/PCl₅ to obtain the following corresponding chlorinatedintermediates such as compounds of formula (IX) and (X), wherein X_(5c),n and Ar₂ are as defined above.

[0384] Furthermore, a compound of formula IX and formula X whereinX_(5c) is a protected amino moiety wherein the protection is effectedwith an acid labile group such as acyl or dibenzylidene can bedeprotected using standard methods such as a strong acid in an alcoholicsolvent such as ethanol or a polar solvent such as ethyl acetate toyield the free amine which can then be chlorinated as above.Alternatively the free amine may be liberated by the action of thePOCl₃, but in either case the free amine may be reprotected with asuitable protecting group such as dibenzylidene.

[0385] A compound of formula XI,

[0386] such as compounds of formulae IX and X, wherein Ar₁, X₅, X_(5a)and X_(5b) are as defined above, and one of X₅, X_(5a) and X_(5b) ischloro at the position alpha to the nitrogen of the distal ring of Ar₁when AR₁ is bicyclic, and the methyl moiety is attached to the proximalring of Ar₁, may be treated with NaBr or an arylhydroxy compound such asphenol and potassium hydroxide to afford a compound of formula XIwherein the chloro at the position alpha to the nitrogen of the distalring of Ar₁ is replaced by bromo or aryloxy at that position.

[0387] The methyl moiety of a compound of formula XI, wherein Ar₁, X₅,X_(5a) and X_(5b) are as defined above, provided that wherein X₅, X_(5a)and X_(5b) is hydroxy or amino bearing a hydrogen then the hydroxy andamino are protected by appropriate hydroxy and/or amino protectinggroups, may be halogenated using standard conditions such asN-halosuccinimide and benzoyl peroxide in an inert solvent such ascarbon tetrachloride to give the corresponding halomethyl compound offormula III wherein L is bromo, chloro, or iodo, and one of X₅, X_(5a)and X_(5b) is chloro, bromo or aryloxy at the position alpha to thenitrogen of the distal ring of Ar₁.

[0388] Alternatively, a compound of formula III wherein

[0389] is

[0390] A is CH, W is NH and Z is methylenyl, L is halo, one of X₅,X_(5a) and X_(5b) is on the 5-membered ring of

[0391] and is a substituent as defined above or one wherein amino orhydroxy moieties thereof are suitably protected, another of X₅, X_(5a)and X_(5b) is on the 6-membered ring of

[0392] and is a substituent as defined above or one wherein amino orhydroxy moieties thereof are suitably protected, and the other of X₅,X_(5a) and X_(5b) is hydrogen, chloro, bromo or aryloxy and issubstituted alpha to the nitrogen in the 6-membered ring of

[0393] may be prepared by reacting a compound of formula XII, formulaXIII or formula XIIIa

[0394] (prepared as described in J. Het. Chem., 29, 359 (1992); Bull.Soc. Chim. Belg. 301 (1970); and J. Med. Chem. 33, 2087 (1990), thecontents of all of which are hereby incorporated herein by reference)wherein W is NH and X₆ is H, with POCl₃ or POCl₃/PCl₅ as described aboveto obtain the corresponding chloro compound. A compound of formula XIIor formula XIII wherein W is NH and X₇ is H can be protected usingstandard methods such as with benzenesulfonyl chloride using a strongbase such as sodium hydroxide in an halogenated solvent such asdichloromethane in the presence of a phase transfer catalyst such astetrabutylammonium chloride to yield a compound of formula XII orformula XIII wherein W is N—SO₂Ph and X₇ is H. These are treated with astrong base such as sodium hydride, lithium hexamethyldisilylazide, orlithium diisopropyl amine in an inert organic solvent such astetrahydrofuran or dimethylformamide at about −78° C. to about 25° C.,followed by the addition of ethyl chloroformate to yield a compound offormula XII or formula XIII wherein W is N—SO₂Ph and X₇ is —CO₂ loweralkyl, which in turn can be converted to a compound of formula XII orformula XIII wherein W is N—SO₂Ph and X₇ is —CH₂OH using standardhydride reducing agents such as lithium aluminum hydride in anappropriate organic solvent such as diethyl ether at about −10° C. toabout 25° C. Then a compound of formula XII or formula XIII wherein W isN—SO₂Ph and X₇, is —CH₂OH may be halogenated using standard conditionssuch as PBr₃ in an organic solvent such as diethyl ether to give acompound of formula III as defined above.

[0395] Alternatively, a compound of formula III may be prepared bycondensing an appropriate beta-aryl or beta-heteroaryl amino acid offormulae XIV or XV,

[0396] wherein W and X₇ are as defined herein, with Gold's reagent underbasic conditions using sodium hydride or another equally strong basefollowed by an acidic work-up. The resulting compound is then processedas described above to yield a compound of formula III.

[0397] A compound of formula II as defined above is treated with astrong base such as sodium hydride, lithium hexamethyldisilylazide, orlithium diisopropyl amine in an inert organic solvent such astetrahydrofuran or dimethylformamide at about −78° C. to about 25° C.followed by the addition of a compound of formula III above wherein oneX₅, X_(5a) and X_(5b) is substituted alpha to a nitrogen of the distalring of

[0398] and is hydrogen, chloro, bromo or aryloxy, and L is a goodleaving group such as chloro, bromo, or iodo, to give a compound offormula IV above.

[0399] Alternatively a compound of formula IV wherein

[0400] is

[0401] A is CH, W is NH and Z is methylenyl, L is halo, one of X₅,X_(5a) and X_(5b) is on the 5-membered ring of

[0402] and is a substituent as defined above or one wherein amino orhydroxy moieties thereof are suitably protected, another of X₅, X_(5a)and X_(5b) is on the 6-membered ring of

[0403] and is a substituent as defined above or one wherein amino orhydroxy moieties thereof are suitably protected, and the other of X₅,X_(5a) and X_(5b) is hydrogen, chloro, bromo or aryloxy and issubstituted alpha to the nitrogen in the 6membered ring of

[0404] may be prepared by alkylation of a(2-oxopyrrolidin-3-(S)-yl)-carbamic acid alkyl or aralkyl ester withpropargyl bromide in the presence of a base such as sodium hydride. Thealkyne that is obtained is heated (100-120° C.) with a halopyridineoptionally substituted with hydroxy, alkoxycarbonylamino, or sulfhydryl,a catalyst such as Pd(PPh₃)₂Cl₂, copper iodide and triethylamine in asuitable solvent such as acetonitrile in a sealed vessel or in DMF, for2-20 hours. When the pyridine is substituted with a hydroxyl moiety,furopyridines are isolated directly if the pyridine is substituted withan alkoxycarbonylamino moiety. Additional treatment with DBU at about60° C. in DMF yields pyrrolopyridines. Subsequent deprotection yieldsthe desired 2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-furopyridines orpyrrolopyridine-1-carboxylic acid alkyl esters. These compounds aresulfonylated in the normal manner (using arene sulfonyl chlorides andbase such as triethylamine) and in the case of furopyridines purified(HPLC) to obtain arenesulfonic acid[2-oxo-1-(furopyridinyl-methyl)pyrrolidine-3-(S)-yl]-amides generally asthe TFA salts. In the case of pyrrolopyridines an additionaldeprotection step (such as acid for BOC protecting groups) yieldscorresponding arenesulfonic acid[2-oxo-1-(pyrrolopyridinyl-methyl)-pyrrolidin-3-(S)-yl]-amides.

[0405] The P₁ moiety of the compound of formula IV is then removed bythe appropriate deprotecting procedures known for carbamates such asstrong acid, strong base or catalytic hydrogenation to give a compoundof formula XVI, wherein Ar₁, X₅, X_(5a), X_(5b), Z and m are as definedabove.

[0406] The amine of the compound of formula XVI liberated by the removalof P₁ is then coupled to a compound of formulae XVII or XVIII

R₃S(O)_(p)Halo   (XVII)

[0407] or

R₃R₄NS(O)_(p)Halo   (XVIII)

[0408] where R₃, R₄, and p are as defined above, and Halo is a halogenatom such as chloro, using a base such as a trialkylamine in an inertsolvent such as dichloromethane, tetrahydrofuran, ether or acetonitrileat about 0° C. to about 100° C. in the presence or absence of anactivating agent such as dimethyl aminopyridine (DMAP) to give acompound of formula XIX

[0409] wherein Ar₁, R₁, R₃, R₄, X₁, X_(1a), X₂, X_(2a), X₃, X₄, X₅,X_(5a), X_(5b), Z and m are as defined above.

[0410] Compounds represented by formula XIX wherein one X₅, X_(5a) andX_(5b) is substituted alpha to a nitrogen of the distal ring of

[0411] and is bromo or chloro may be converted to the correspondingaryloxide by reaction with an arylhydroxy compound such as phenol, and astrong alkali base such as potassium hydroxide at 70° C. to about 120°C. The aryloxide intermediate (Y═ArO—) is then treated with an ammoniumsalt such as ammonium acetate at about 90° C. to 180° C. to give acompound of formula I wherein Ar₁, R₁, R₃, R₄, X₁, X_(1a), X₂, X_(2a),X₃, X₄, X₅, X_(5a), X_(5b), Z and m are as defined above, and whereinone X₅, X_(5a) and X_(5b) is substituted alpha to a nitrogen of thedistal ring of

[0412] and is NH₂.

[0413] Alternatively, a compound of formula XIX wherein one X₅, X_(5a),and X_(5b) is substituted alpha to a nitrogen of the distal ring of

[0414] and is bromo or chloro may be treated with an arylhydroxy such asphenol and an ammonium salt such as ammonium acetate at about 90° C. to180° C. to give compounds represented by formula I wherein Ar₁, R₁, R₃,R₄, X₁, X_(1a), X₂, X_(2a), X₃, X₄, X₅, X_(5a), X_(5b), Z and m are asdefined above, and wherein one X₅, X_(5a) and X_(5b) is substitutedalpha to a nitrogen of the distal ring of

[0415] and is NH₂.

[0416] Alternatively, a compound of formula I may be prepared startingwith a compound of formula XX.

[0417] wherein X₃, X₄, P₁ and m are as defined above, and P₂ is alkyl,aralkyl or aryl, by reductive amination using a (heteroaryl)alkylamineof formula XXI

[0418] wherein Ar₁, X₅, X_(5a), X_(5b) and Z are as defined above, in analcoholic solvent such as methanol and an imine reducing reagent such assodium cyanoborohydride or sodium triacetoxyborohydride at about 0° C.to about 100° C. to give the cyclic structure represented by formula IVwhich is then converted to a compound of formula I as described above.

[0419] A compound of formula XXI used in the reductive aminationdescribed above may be prepared by treatment of a compound of formulaIII wherein one of X₅, X_(5a), X_(5b) is H or aryloxy at the positionalpha to the nitrogen of the distal ring of Ar₁, and L is a leavinggroup such as chloro, bromo, iodo or the like, with sodium azidefollowed by reduction using standard reducing methods such astriphenylphosphine in solvents such as water/tetrahydrofuran orcatalytic reduction.

[0420] A compound of formula I in which R₁ is other than H may beprepared starting with a compound of formula I wherein R₁ is H bydissolving it in an inert organic solvent such as tetrahydrofuran,dioxane, or dimethyl formamide at about 0° C. to about 100° C. To theresulting solution is added a base such as sodium hydride or potassiumcarbonate and a compound of formula XXII.

R₁-Halo   XXII

[0421] wherein R₁ is as defined above except that R₁ is not H, and Halois a halogen such as bromo or chloro.

[0422] A compound of formula I including an heteroaryl group containingone or more nitrogen ring atoms, preferably imine (═N—), may beconverted to the corresponding compound wherein one or more nitrogenring atom of the heteroaryl moiety is oxidized to an N-oxide, preferablyby reacting with a peracid, for example peracetic acid in acetic acid orm-chloroperoxybenzoic acid in an inert solvent such as dichloromethane,at a temperature from about room temperature to reflux, preferably at anelevated temperature.

[0423] The compounds of the present invention are useful in the form ofthe free base or acid or in the form of a pharmaceutically acceptablesalt thereof. All forms are within the scope of the invention.

[0424] Where a compound of the present invention is substituted with abasic moiety, acid addition salts are formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free base form. The acids which can beused to prepare the acid addition salts include preferably those whichproduce, when combined with the free base, pharmaceutically acceptablesalts, that is, salts whose anions are non-toxic to the patient inpharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on the activity of Factor Xa inherent in the free base are notvitiated by side effects ascribable to the anions. Althoughpharmaceutically acceptable salts of said basic compounds are preferred,all acid addition salts are useful as sources of the free base form evenif the particular salt, per se, is desired only as an intermediateproduct as, for example, when the salt is formed only for purposes ofpurification, and identification, or when it is used as intermediate inpreparing a pharmaceutically acceptable salt by ion exchange procedures.Pharmaceutically acceptable salts within the scope of the invention arethose derived from the following acids: mineral acids such ashydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; andorganic acids such as acetic acid, citric acid, lactic acid, tartaricacid, malonic acid, methanesufonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid,quinic acid, and the like. The corresponding acid addition salts includethe following: hydrohalides, e.g. hydrochloride and hydrobromide,sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate,tartarate, malonate, oxalate, salicylate, propionate, succinate,fumarate, maleate, methylene-bis-B-hydroxynaphthoates, gentisates,mesylates, isothionates and di-p-toluoyltartrates, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate, respectively.

[0425] According to a further feature of the invention, acid additionsalts of the compounds of this invention are prepared by reaction of thefree base with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

[0426] The compounds of this invention may be regenerated from the acidaddition salts by the application or adaptation of known methods. Forexample, parent compounds of the invention can be regenerated from theiracid addition salts by treatment with an alkali, e.g. aqueous sodiumbicarbonate solution or aqueous ammonia solution.

[0427] Where a compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on the activity of Factor Xa inherent in the free acid are notvitiated by side effects ascribable to the cations. Pharmaceuticallyacceptable salts, including for example alkali and alkaline earth metalsalts, within the scope of the invention are those derived from thefollowing bases: sodium hydride, sodium hydroxide, potassium hydroxide,calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesiumhydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine,lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)aminomethane,tetramethylammonium hydroxide, and the like.

[0428] Metal salts of compounds of the present invention may be obtainedby contacting a hydride, hydroxide, carbonate or similar reactivecompound of the chosen metal, in an aqueous or organic solvent, with thefree acid form of the compound. The aqueous solvent employed may bewater or it may be a mixture of water with an organic solvent,preferably an alcohol such as methanol or ethanol, a ketone such asacetone, an aliphatic ether such as tetrahydrofuran, or an ester such asethyl acetate. Such reactions are normally conducted at ambienttemperature but they may, if desired, be conducted with heating.

[0429] Amine salts of compounds of the present invention may be obtainedby contacting an amine in an aqueous or organic solvent with the freeacid form of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitriles such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

[0430] The base addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their base addition salts by treatment with an acid,e.g. hydrochloric acid.

[0431] Salt forms according to invention also include compounds having aquarternarized nitrogen. The quarternarized salts are formed by methodssuch as by alkylation of a sp³ or sp² hybridized nitrogen in thecompounds.

[0432] As will be self-evident to those skilled in the art, some of thecompounds of this invention do not form stable salts. However, acidaddition salts are most likely to be formed by compounds of thisinvention having a nitrogen-containing heteroaryl group and/orpossessing an amino group as a substituent. Preferable acid additionsalts of the compounds of the invention are those wherein there is notan acid labile group.

[0433] As well as being useful in themselves as active compounds, saltsof compounds of the invention are useful for the purposes ofpurification of the compounds, for example by exploitation of thesolubility differences between the salts and the parent compounds, sideproducts and/or starting materials by techniques well known to thoseskilled in the art.

[0434] Compounds of the present invention may contain asymmetriccenters. These asymmetric centers may independently be in either the (R)or (S) configuration. It will also be apparent to those skilled in theart that certain compounds of formula I may exhibit geometricalisomerism. Geometrical isomers include the cis and trans forms ofcompounds of the invention having an alkenyl moiety. The presentinvention comprises the individual geometrical isomers and stereoisomersand mixtures thereof.

[0435] Such isomers can be separated from their mixtures by theapplication or adaptation of known methods, for example, chromatographictechniques and recrystallization techniques, or they are separatelyprepared from the appropriate isomers of their intermediates, forexample by the application or adaptation of methods described herein.

[0436] The starting materials and intermediates are prepared by theapplication or adaptation of known methods, for example methods asdescribed in the Reference Examples or their obvious chemicalequivalents.

[0437] The present invention is further exemplified but not limited bythe following examples, which illustrate the preparation of thecompounds according to the invention.

[0438] In the nuclear magnetic resonance spectra (NMR) the chemicalshifts are expressed in ppm relative to tetramethylsilane. Abbreviationshave the following significance: s=singlet; d=doublet; t=triplet;m=multiplet; dd=doublet of doublets; ddd=doublet of doublets ofdoublets; dt=doublet of triplets, b=broad, bs=broad singlet, q=quartet,AB=AB pattern.

EXAMPLE 1

[0439] 7-Methoxynaphthalene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3(R,S)-yl]-amidetrifluoroacetate

[0440] A. 3-p-Tolyl-acryloyl chloride

[0441] Thionyl chloride (9.44 mL, 129.5 mmol) is added dropwise to asolution of 3-p-tolyl-acrylic acid (20 g, 123.3 mmol) in benzene (50 mL)at 0° C. The resulting solution is allowed to warn to room temperaturethen heated to reflux for 2 hours. The mixture is concentrated todryness on the rotovap to give the crude product (22.3 g, 123.3 mmol)which is taken onto the next step.

[0442]¹H NMR (CDCl₃, 300 MHz) δ7.80 (d, 1H), 7.50 (d, 2H), 7.26 (d, 2H),6.58 (d, 1H), 2.40 (s, 3H).

[0443] B. 3-p-Tolyl-acryloyl azide

[0444] 3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane (50mL) is slowly added to an ice cooled solution of sodium azide (16 g,246.6 mmol) in water/dioxane (50 mL, 1/1, v/v) so as to maintain thetemperature between 5-10° C. The mixture is stirred for 1.5 hours thenpoured over 300 g of ice. The resulting white solid is filtered andwashed with additional water. The solid (20.72 g, 110.7 mmol) was driedover P₂O₅ under vacuum overnight and used in the next step withoutfurther purification.

[0445]¹H NMR (CDCl₃, 300 MHz) δ7.73 (d, 1H), 7.45 (d, 2H), 7.21 (d, 2H),6.38 (d, 1H), 2.38 (s, 3H). EI MS, [M.]⁺=187.

[0446] C. 1-(2-Isocyanato-vinyl)-4-methyl-benzene

[0447] 3-p-Tolyl-acryloyl azide (20.72 g, 110.7 mmol) in benzene (100mL) is heated slowly to 75° C. for 3.5 hours then concentrated to give abrown oil (ca. 20 g). This material was taken onto the next step withoutfurther purification.

[0448]¹H NMR (CDCl₃, 300 MHz) δ7.18 (d, 2H), 7.12 (d, 2H), 6.53 (d, 1H),6.40 (d, 1H), 2.32 (s, 3H). EI MS, [M.]⁺=159.

[0449] D. 7-Methyl-2H-isoquinolin-1-one

[0450] Iodine (0.63 g, 2.51 mmol) is added to a solution of1-(2-isocyanato-vinyl)4-methyl-benzene (ca. 20 g, 125.6 mmol) ino-dicblorobenzene (125 mL), then is heated io reflux (180° C.)overnight. The mixture is cooled to room temperature then concentratedto dryness. The residue is purified by column chromatography elutingwith 40% EtOAc/hexanes. The product (6.23 g, 39.1 mmol) is obtained as atan solid.

[0451]¹H NMR (CDCl₃, 300 MHz) δ12.25 (bs, 1H), 8.21 (s, 1H), 7.42 (bs,2H), 7.14 (d, 1H), 6.50 (d, 1H), 2.46 (s, 3H). EI MS, [M.]⁺159.

[0452] E. 1-Chloro-7-methylisoquinoline

[0453] 7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in phosphorusoxychloride (30 mL) is heated to reflux for 13 hours. The mixture iscooled to room temperature, then concentrated to a smaller volume. Theresidue is diluted with ice water and the pH is adjusted to ca. 8 byslow addition of 10 N NaOH. The aqueous solution is extracted withmethylene chloride (4×20 mL) and the combined organic layers are washedwith brine, dried over MgSO₄, filtered and concentrated. The resultingdark oil is purified by column chromatography eluting with 25%EtOAc/hexanes to give the product (1.6 g, 9 mmol) as a light yellowsolid.

[0454]¹H NMR (CDCl₃, 300 MHz) δ8.18 (d, 1H), 8.05 (d, 1H), 7.71 (d, 1H),7.55 (m, 2H), 7.55 (s, 3H). EI MS, [M.]⁺177, 179, Cl pattern.

[0455] F. 7-Bromomethyl-1-chloro-isoquinoline

[0456] N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide (0.39 g, 1.13 mmol) are added to a solution of1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon tetrachloride(70 mL). The resulting mixture is heated to reflux for 6 hours thencooled to room temperature and diluted with methylene chloride. Theorganic layer is washed with IN NaOH and brine, then dried over MgSO₄,filtered and concentrated. The residue is purified by columnchromatography eluting with a gradient of 10% EtOAc/hexanes to 25%EtOAc/hexanes to give the product (1.4 g, 5.46 mmol) as a white solid.

[0457]¹H NMR(CDCl₃, 300 MHz) δ8.31 (s, 1H), 8.28 (d, 1H), 7.86 (d, 1H),7.77 (dd, 1H), 7.58 (d, 1H), 4.69 (s, 2H). EI MS, [M.]⁺=255, 257, Cl, Brpattern.

[0458] G.(2-Oxopyrrolidin-3-(S)-yl carbamic acid tert-butyl ester

[0459] (S)Boc-Diaminobutyric acid (25 g, 115 mmol), triethylamine (35 g,344 mmol), and hydroxybenzotriazole (19.3 g, 143 mmol) are dissolved inTHF (300 mL). 1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride(27.4 g, 143 mmol) is added to the solution. The solution is heated to60° C. over 15 minutes. A white precipitate forms and the solution iskept at 60° C. for 4 hours. After this time, the solution is filteredand the collected liquid is concentrated. The crude product is purifiedby column chromatography in a gradient of 1% MeOH/CH₂Cl₂ to 3%MeOH/CH₂Cl₂ to afford the title compound (19.6 g, 98 mmol) as a whitesolid.

[0460]¹H NMR (CDCl₃, 300 MHz) δ6.17 (bs, 1H), 5.08 (bs, 1H), 4.12 (m,1H), 3.33 (m, 2H), 2.65 (m, 1H), 2.00 (m, 1H), 1.42 (s, 9H).

[0461] H.[1-(1-Chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-carbamicacid tert-butyl ester

[0462] Sodium hydride (0.24 g, 6.05 mmol, 60% mineral oil dispersion) isadded to a solution of [2-oxopyrrolidin-3(S)-yl]-carbamic acidtert-butyl ester (1.18 g, 5.89 mmol) in THF/DMF (62 mL, 9/1, v/v) at 0°C. The mixture is stirred for 2 minutes, then a solution of7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10 mL) isadded dropwise via a cannula. The resulting yellow solution is stirredfor 1 hour at 0° C. then at room temperature for 3 hours. The reactionmixture is quenched with saturated ammonium chloride solution, thendiluted with EtOAc. The organic layer is washed with water and brine,then dried over MgSO₄, filtered and concentrated. The residue ispurified by column chromatography eluting with a gradient of 50%EtOAc/hexanes to 70% EtOAc/hexanes to give the product (1.67 g, 4.44mmol) as a foamy white solid.

[0463]¹H NMR (CDCl₃, 300 MHz) 67 8.25 (d, 1H), 8.12 (s, 1H), 7.83 (d,1H), 7.68 (dd, 1H), 7.58 (d, 1H), 5.55 (bs, 1H), 4.71 (AB, 2H), 4.30 (m,1H), 3.26 (m, 2H), 2.60 (m, 1H), 1.98 (m, 1H), 1.46 (s, 9H). EI MS,[M+H]⁺=376, 378, Cl pattern.

[0464] I.3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride

[0465] To a solution of[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-carbamicacid tert-butyl ester (2.1 g, 5.6 mmol) in EtOAc (170 mL) at 0° C. isbubbled HCl gas for 5 minutes. The solution is stirred at 0° C. for 15minutes, then the ice bath is removed and the solution allowed to warmto room temperature. After 4 hours at room temperature, the solution isconcentrated and the remaining solid is washed with ether to give thetitle compound (1.74 g, 5.6 mmol) as a pale yellow solid.

[0466]¹H NMR (DMSO-d₆, 300 MHz) δ8.64 (d, 3H), 8.31 (d, 1H), 8.18 (s,1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 4.71 (AB, 2H), 4.10 (m,1H), 3.30 (m, 2H), 2.41 (m, 1H), 1.98 (m, 1H). FAB MS, [M+H]⁺=276.

[0467] J. 7-Methoxynaphthalene-2-sulfonyl chloride

[0468] To a suspension of 7-hydroxynaphthalene-2-sulfonic acid, sodiumsalt (15 g, 60.9 mmol) in H₂O/ethanol (150 mL, 2:1) is added solid NaOH(2.68 g, 67 mmol) at room temperature. The mixture is stirred until ahomogenous solution forms and dimethyl sulfate (6.34 mL, 67 mmol) isthen added. A precipitate slowly forms and the mixture is stirred over aperiod of 16 hours. The crude mixture is concentrated in vacuo and theresidue is stirred in absolute EtOH (100 mL) as a slurry for 2 hours.The precipitate is filtered and dried. The solid is heated at reflux in95% EtOH (100 mL) for 2 h, allowed to cool to room temperature, filteredand dried to give 12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid,sodium salt. A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6mmol) in phosphorous oxychloride (20 mL) and phosphorous pentachloride(13.2 g, 63.2 mmol) is heated slowly to 60° C. until a homogenoussolution forms and then is heated at 120° C. for 4 hours. The resultingmixture is cooled in an ice bath and a mixture of ice/ice water is addedslowly with stirring. The mixture is diluted with water and extractedwith CHCl₃ (2×100 mL). The combined organic layers are washedsuccessively with water, saturated NaHCO₃ solution and saturated NaCl.The organic phase is dried over anhydrous MgSO₄, filtered andconcentrated to give 10 g of a crude oil. The crude product is purifiedby column chromatography in a gradient of 5% EtOAc/hexanes to 30%EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a whitecrystalline solid.

[0469]¹H NMR (CDCl₃, 300 MHz) δ8.49 (d, 1H), 7.96 (d, 1H), 7.85 (d, 2H),7.39 (dd, 1H), 7.29 (d, 1H), 3.99 (s, 3H). EI MS, [M]⁺256.

[0470] K. 7-Methoxynaphthalene-2-sulfonic acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0471] 3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (1.74 g, 5.6 mmol) is suspended in CH₃CN (120 mL). To thissolution is added triethylamine (2.35 mL, 16.9 mmol) followed by7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.93 mmol). Themixture is stirred overnight, then concentrated to dryness. The crudeproduct is purified by column chromatography eluting with a gradient of2% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give the title compound (2.7 g, 5.4mmol) as a light yellow solid.

[0472]¹H NMR (CDCl₃, 300 MHz) δ8.35 (d, 1H), 8.27 (d, 1H), 8.08 (s, 1H),7.91 (d, 1H), 7.80 (d, 1H), 7.78 (s, 1H), 7.74 (dd, 1H), 7.56 (s, 1H),7.51 (d, 1H), 7.30 (dd, 1H), 7.24 (d, 1H), 5.42 (d, 1H), 4.63 (AB, 2H),3.95 (s, 3H), 3.78 (m, 1H), 3.25 (m, 2H), 2.60 (m, 1H), 2.08 (m, 1H).FAB MS, [M+H]⁺=496, 498, Cl pattern.

[0473] L. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-amide

[0474] Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g, 7.31mmol) are added to 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(1.8 g, 3.6 mmol) and heated to 90° C. until a homogeneous mixture isobtained. The mixture is stirred overnight at 90° C., then cooled toroom temperature and diluted with methylene chloride (100 mL) and water.The aqueous layer is neutralized to pH 7 using 1 N HCl, then the twolayers are separated and the aqueous layer is extracted with additionalmethylene chloride. The combined organic layers are washed with brine,dried over MgSO₄, filtered and concentrated. The residue is purified bycolumn chromatography eluting with a gradient of 30% EtOAc/hexanes to60% EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white solid.

[0475]¹H NMR (CDCl₃, 300 MHz) δ8.40 (s, 1H), 8.20 (s, 1H), 7.94 (d, 1H),7.82 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.51 (dd, 1H), 7.40 (m, 2H),7.15-7.30 (m, 7H), 5.80 (bs, 1H), 4.60 (AB, 2H), 3.98 (s, 3H), 3.82 (m,1H), 3.20 (m, 2H), 2.52 (m, 1H), 2.04 (m, 1H). FAB MS, [M+H]⁺=554.

[0476] M. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(RS)-yl]-amidetrifluoroacetate

[0477] In around-bottomed flask fitted with a water condenser,7-methoxynaphthalene-2-sulfonicacid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrtolidin-3-(S)yl]-amide(0.318 g, 0.574 mmol) and ammonium acetate (5 g, 65 mmol) are heated to160° C. After ca. 6 hours, the homogeneous mixture is cooled to roomtemperature and the mixture is purified by RP-HPLC eluting with agradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. The appropriatefractions are lyophilized to give the title racemic compound (0.157 g,0.266 mmol) as a white solid.

[0478]¹H NMR (DMSO-d₆, 300 MHz) δ8.95 (bs, 2H), 8.39 (s, 1H), 8.23-8.29(m, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.74(dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.35 (dd, 1H), 7.24 (d, 1H), 4.56(AB, 2H), 4.20 (m, 1H), 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, 1H), 1.60(m, 1H). FAB MS, [M+H]⁺=477.

EXAMPLE 2

[0479] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amidehydrochloride

[0480] In a round-bottomed flask fitted with a cold finger condenser,phenol (0.569 g, 6 mmol) and 7-methoxy-naphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.2 g, 0.4 mmol) is melted at 70° C. The mixture is stirred for 5minutes, then ammonium acetate (0.462 g, 6 mmol) is added and heated at115° C. for 2 hours. After this time, additional ammonium acetate (0.462g, 6 mmol) is added. After 2 hours the reaction mixture is cooled toroom temperature then partitioned between EtOAc and 0.5N NaOH. Theorganic layer is separated and washed with water and brine, then driedover Na₂SO₄, filtered and concentrated. The resulting residue ispartially purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate fractions are concentrated invacuo. The solid which precipitates out from the solution is thenfiltered, dried and purified again by column chromatography eluting with5% MeOH/CH₂Cl₂. This product is then triturated with cold MeOH and thecollected solid is suspended in MeOH and cooled to 0° C. HCl(g) isbubbled through the slurry for a few minutes during which time all thesolid dissolves into the solution. The solvent is removed in vacuo andthe title product (0.11 g, 0.214 mmol) is washed with ether and dried.

[0481]¹H NMR (DMSO-d₆, 300 MHz) δ13.30 (bs, 1H), 9.18 (bs, 2H), 8.32 (s,1H), 8.25 (d, 1H), 7.99 (d, 1H), 7.85-7.91 (m, 2H), 7.60-7.80 (m, 3H),7.50 (s, 1H), 7.25 (dd, 1H), 7.18 (d, 1H), 4.51 (AB, 2H), 4.23 (m, 1H),3.85 (s, 3H), 3.12 (m, 2H), 1.95 (m, 1H), 1.65 (m, 1H). FAB MS,[M+H]⁺=477. Melting point: 187-192° C. The enantiomeric purity is 88% eeas determined by analytical Chiralpak AD reverse phase HPLC.

EXAMPLE 3

[0482]7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0483] The title compound is prepared by resolution of the racemiccompound described in EXAMPLE 1, Part M using a Chiralpak AD HPLC column(55% EtOH/Heptane(0.1% TFA)).

[0484]¹H NMR (DMSO-d₆, 300 MHz) δ8.95 (bs, 2H), 8.39 (d, 1H), 8.30 (s,1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.93 (d, 1H), 7.77 (d,1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.35 (dd, 1H), 7.24 (d,1H), 4.56 (AB, 2H), 4.20 (m, 1H), 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m,1H), 1.60 (m, 1H). FAB MS, [M+H]⁺=477. The enantiomeric purity is 96.3%ee as determined by analytical Chiralpak AD reverse phase HPLC.[a]_(D)+3.16° (MeOH). cl EXAMPLE 4

[0485]7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R)-yl]-amidetrifluoroacetate

[0486] The title compound is prepared by resolution of the racemiccompound described in EXAMPLE 1, Part M using a Chiralpak AD HPLC column(55% EtOH/Heptane (0.1% TFA)).

[0487]¹H NMR (DMSO-d₆, 300 MHz) δ8.95 (bs, 2H), 8.39 (d, 1H), 8.30 (s,1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.93 (d, 1H), 7.77 (d,1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.35 (dd, 1H), 7.24 (d,1H), 4.56 (AB, 2H), 4.20 (m, 1H), 3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m,1H), 1.60 (m, 1H). FAB MS, [M+H]⁺477. The enantiomeric purity is 90.7%ee as determined by analytical Chiralpak AD reverse phase HPLC.[a]_(D)−3.89° (MeOH).

EXAMPLE 5

[0488]7-Methoxynaphthalene-2-sulfonicacid[1-(1-hydroxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3(R,S)-yl]amide

[0489] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide(0.07 g, 0.14 mmol), prepared as described in EXAMPLE 1, Part K , istreated with dioxane (1 mL) and 10% aq. NaOH (3 mL) and heated to refluxfor 48 hours. The reaction was cooled, acidified with 1 N HCl andextracted with CH₂Cl₂. The organic layer is separated, dried andconcentrated. The residue is purified by column chromatography elutingwith 2.5% MeOH/CH₂Cl₂. The product fractions are collected, concentratedand precipitated with dilute HCl/ether to yield the title compound(0.041 g, 0.086 mmol).

[0490]¹H NMR (CD₃OD, 300 MHz) δ8.41 (s, 1H), 8.25 (d, 1H), 8.06 (bs,1H), 7.93 (d, 1H), 7.85 (d, 1H), 7.76 (d, 1H), 7.58 (AB, 2H), 7.39 (s,1H), 7.24 (dd, 1H), 7.17 (d, 1H), 6.66 (bs, 1H), ), 4.55 (AB, 2H), 4.20(m, 1H), 3.92 (s, 3H), 3.19 (m, 2H), 2.20 (m, 1H), 1.59 (m, 1H), 1.70(m, 1H). FAB MS, [M+H]⁺=478. Elemental analysis calculated with 1.6 moleof H₂O: C=58.42%, H=4.71%, N=8.18%; found C=59.30%, H=5.04%, N=7.96%.

EXAMPLE 6

[0491] 7-Methoxynaphthalene-2-sulfonicacid-[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamidetrifluoroacetate

[0492] A. 7-Methoxynaphthalehe-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamideTo a solution of 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.1 51 g, 0.304 mmol) in acetone (20 mL) is added potassium carbonate(0.084 g, 0.608 mmol) followed by methyl iodide (0.12 mL, 1.93 mmol).The resulting mixture is heated to reflux overnight, then cooled to roomtemperature and diluted with methylene chloride. The solution is washedwith saturated NaHCO₃ solution, water and brine. The organic layer isdried over MgSO₄, filtered and concentrated. The residue is purified bycolumn chromatography eluting with 5% MeOH/CH₂Cl₂ to give the product(0.093 mg, 0.18 mmol) as an oil.

[0493]¹H NMR (CDCl₃, 300 MHz) δ8.41 (s, 1H), 8.04 (s, 1H), 8.23-8.26 (m,2H), 8.07 (s, 1H), 7.90 (d, 1H), 7.90 (d, 1H), 7.77 (s, 1H), 7.75 (s,1H), 7.58 (dd, 1H), 7.28 (m, 1H), 5.02 (m, 1H), 4.63 (AB, 2H), 3.92 (s,3H), 3.24 (m, 2H), 2.82 (s, 3H), 2.32 (m, 1H), 2.05 (m, 1H).

[0494] B. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamide

[0495] The title compound is prepared as described in EXAMPLE 1, Part Lusing 7-methoxynaphthalene-2-sulfonic acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamidein place of 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.

[0496]¹H NMR (CDCl₃, 300 MHz) δ8.45 (s, 1H), 8.20 (s, 1H), 7.90 (d, 1H),7.81 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.54 (dd, 1H), 7.38-7.45 (m,3H), 7.14-7.30 (m, 6H), 5.00 (m, 1H), 4.62 (AB, 2H), 3.88 (s, 3H), 3.25(m, 2H), 2.81 (s, 3H), 2.30 (m, 1H), 2.01 (m, 1H).

[0497] C. 7-Methoxynaphthalene-2-sulfonicacid-[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamidetrifluoroacetate

[0498] The title compound is prepared as described in EXAMPLE 1, Part Musing 7-methoxynaphthalene-2-sulfonic acid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)yl]-methyl-amidein place of 7-methoxynaphthalene-2-sulfonicacid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-amide.

[0499]¹H NMR (DMSO-d₆, 300 MHz) δ9.00 (bs, 2H), 8.40 (s, 1H), 8.26 (s,1H), 8.04 (d, 1H), 7.90-7.95 (m, 2H), 7.79 (d, 1H), 7.71 (dd, 1H), 7.65(d, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 4.95 (m, 1H), 4.54(AB, 2H), 3.86 (s, 3H), 3.20 (m, 2H), 2.65 (s, 3H), 2.00 (m, 1H), 1.75(m, 1H). FAB MS, [M+H]⁺=491. Elemental analysis calculated with 1.5 moleof H₂O: C=53.25%, H=4.79%, N=8.87%, found C=53.43%, H=4.50%, N=8.58%.

EXAMPLE 7

[0500] 7-Methoxynaphthalene-2-sulfonicacid-[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamidetrifluoroacetate

[0501] The title compound is prepared by resolution of the racemiccompound described in EXAMPLE 6, Part C using a Chiralpak AD reversephase HPLC column (55% EtOH/Heptane(0. 1% TFA)).

[0502]¹H NMR (DMSO-d₆, 300 MHz) δ13.5 (bs, 1H), 9.20 (bs, 2H), 8.40 (s,1H), 8.26 (s, 1H), 8.04 (d, 1H), 7.90-8.00 (m, 2H), 7.79 (d, 1H), 7.71(dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.34 (dd, 1H), 7.23 (d, 1H), 4.98(m, 1H), 4.54 (AB, 2H), 3.86 (s, 3H), 3.20 (m, 2H), 2.68 (s, 3H), 2.05(m, 1H), 1.80 (m, 1H). FAB MS, [M+H]⁺=491. The enantiomeric purity is92.6% ee as determined by analytical Chiralpak AD reverse phase HPLC.

EXAMPLE 8

[0503] Benzo[b]thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0504] A. Benzo[bthiophene-2-sulfonyl chloride

[0505] To a solution of thianaphthalene (11.8 g, 88.1 mmol), in THF (400mL) at −78° C. is added n-BuLi (55 mL of a 1.6 M solution in hexanes,88.1 mmol). After 15 minutes, the solution is added by cannula to aprecooled (−78° C.) solution of SO₂ (200 g) in THF (100 mL). Afteraddition, the solution is allowed to warm to ambient temperatures. After0.5 h, the solution is concentrated. The residue is suspended in hexanes(400 mL) and is cooled to 0° C. To the solution is added SO₂Cl₂ (12.5 g,92.5 mmol). After stirring for 15 minutes, the solution is concentrated.The residue is dissolved in EtOAc. The organic solution is washed withsatuated NH₄Cl (aq.), H₂O and saturated NaCl (aq.). The organic layer isdried over MgSO₄, filtered and concentrated. The crude product isdissolved in CH₂Cl₂ and filtered through a plug of silica gel. Theorganic solution is then concentrated. The resulting solid is trituratedwith hexane to give the title compound (12.1 g, 38 mmol).

[0506]¹H NMR (CDCl₃, 300 MHz) δ8.16 (s, 1H), 7.97 (m, 2H), 7.57 (m, 2H).

[0507] B. Benzo[b]thiophene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0508] The title compound is prepared as described in EXAMPLE 1, Part Kusing benzo[b]thiophene-2-sulfonyl chloride in place of7-methoxynaphthalene-2-sulfonyl chloride.

[0509]¹H NMR (CDCl₃, 300 MHz) δ8.29 (d, 1H), 8.12 (s, 1H), 7.93 (s, 1H),7.84-7.92 (m, 2H), 7.82 (d, 1H), 7.54-7.62 (m, 2H), 7.46-7.52 (m, 2H),5.50 (d, 1H), 4.66 (AB, 2H), 3.95 (m, 1H), 3.25 (m, 2H), 2.65 (m, 1H),2.15 (m, 1H).

[0510] FAB MS, [M+H]⁺472, 474, Cl pattern.

[0511] C. Benzo[b]thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0512] The Title compound was prepared as described in EXAMPLE 2 usingbenzo[b]thiophene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideas the starting material. No extractive work up is performed. The crudeproduct is purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate fractions are lyophilized toprovide the title compound as a white solid.

[0513]¹H NMR (DMSO-d₆, 300 MHz) δ9.00 (bs, 2H), 8.65 (d, 1H), 8.30 (s,1H), 8.07-8.15 (m, 3H), 8.05 (d, 1H), 7.94 (d, 1H), 7.80 (d, 1H), 7.68(d, 1H), 7.45-7.58 (m, 2H), 7.22 (d, 1H), 4.55 (AB, 2H), 4.31 (m, 1H),3.25 (m, 2H), 2.20 (m, 1H), 1.73 (m, 1H). FAB MS, [M+H]⁺=453.

EXAMPLE 9

[0514] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0515] A. 1-Chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene

[0516] To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in THF(200 mL) at 0° C. is added bromoacetaldehyde dimethyl acetal (2.8 g,16.6 mmol). To the solution is added sodium hydride (0.70 g, 17.4 mmol,60% mineral oil dispersion). The reaction is stirred for 16 hours, thenquenched by the addition of saturated NH₄Cl (aq.). The solution isdiluted with EtOAc. The organic layer is washed with saturated NaCl(aq.). The organic layer is dried over MgSO₄, filtered and concentrated.The crude product is purified by column chromatography eluting withhexanes. The title compound (3.7 g, 15.9 mmol) is obtained as an oil.

[0517]¹H NMR (CDCl₃, 300 MHz) δ7.32 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H),4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).

[0518] B. 4Chloro-benzo[b]-thiophene and 6-chloro-benzo[b]-thiophene

[0519] A solution containing polyphosphoric acid (8 g) and chlorobenzene(50 mL) is heated to reflux. A solution containing1-chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene (2.7 g, 11.6 mmol) inchlorobenzene (5 mL) is added dropwise to the refluxing polyphosphoricacid solution. After 6 hours, the solution is cooled to ambienttemperatures. The solution is diluted with CH₂Cl₂ and washed with waterand saturated NaCl (aq.). The organic layer is dried over MgSO₄,filtered and concentrated. The crude product is purified by columnchromatography eluting with hexanes to yield the title compounds (2.4 g,9 mmol) as a 1:1 isomeric mixture.

[0520]¹H NMR (CDCl₃, 300 MHz) δ7.88 (m, 1H), 7.75 (m, 2H), 7.42 (m, 2H).EI MS, [M]⁺=168, 170, Cl pattern.

[0521] C. 6-Chloro-benzo[b]thiophene-2-sulfonyl chloride

[0522] The title compound is prepared as described in EXAMPLE 8, Part Asubstituting the 4-chloro-benzo[b]-thiophene and6Chloro-benzo[b]-thiophene mixture for thianaphthalene. The crudeproduct is purified by column chromatography eluting with hexanes toyield the title compound as well as 4-chlorobenzo[b]thiophene-2-sulfonylchloride as white solids.

[0523] 6-Chloro-benzo[b]thiophene-2-sulfonyl chloride

[0524]¹H NMR (CDCl₃, 300 MHz) δ8.11 (s, 1H), 7.88 (m, 2H), 7.50 (m, 1H).

[0525] 4-Chloro-benzo[b]thiophene-2-sulfonyl chloride

[0526]¹H NMR (CDCl₃, 300 MHz) δ8.32 (m, 1H), 7.81 (m, 1H), 7.53 (m, 2H).

[0527] D. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0528] The title compound is prepared as in EXAMPLE 1, Part K using6-chloro-benzo[b]thiophene-2-sulfonyl chloride in place of7-methoxynaphthalene-2-sulfonyl chloride.

[0529]¹H NMR (CDCl₃, 300 MHz) δ8.29 (d, 1H), 8.12 (s, 1H), 7.91 (s, 1H),7.87 (m, 1H), 7.83 (d, 1H), 7.80 (d, 1H), 7.60 (d, 1H), 7.58 (dd, 1H),7.42 (dd, 1H), 5.50 (d, 1H), 4.65 (AB, 2H), 3.95 (m, 1H), 3.25 (m, 2H),2.65 (m, 1H), 2.15 (m, 1H).

[0530] FAB MS, [M+H]⁺506, 508, Cl pattern.

[0531] E. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0532] The title compound is prepared as described in EXAMPLE 2 using6-Chloro-benzo[b]thiophene-2-sulfonic acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide asthe starting material. No extractive work up is performed. The crudeproduct is purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate fractions are lyophilized toprovide the title compound as a solid.

[0533]¹H NMR (DMSO-d₆, 300 MHz) δ9.00 (bs, 2H), 8.71 (d, 1H), 8.29 (bs,2H), 8.05 (s, 1H), 8.01 (d, 1H), 7.94 (d, 1H), 7.80 (d, 1H), 7.65 (d,1H), 7.55 (dd, 1H), 7.21 (d, 1H), 4.58 (AB, 2H), 4.30 (m, 1H), 3.20 (m,2H), 2.20 (m, 1H), 1.75 (m, 1H).

[0534] FAB MS, [M+H]⁺=487, 489, Cl pattern.

EXAMPLE 10

[0535] 7-Methoxynaphthalene-2-sulfonic acid1-(1-amino-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidehydrochloride

[0536] A. 6Methoxy-7-methyl-2H-isoquinolin-1-one

[0537] 3-(3-Methoxy-4-methylphenyl)propenoic acid (5.33 g, 27.7 mmol)(prepared according to the procedure described in J. Med. Chem. 1991,34, 1662-1668) is suspended in benzene (30 mL) and treated dropwise withthionyl chloride (2.22 mL, 30.5 mmol) at 0° C. The reaction is heated toreflux and it is maintained for 1 hour. The volatiles are removed invacuo and the resulting solid is dissolved in dioxane and added dropwiseto a mixture of sodium azide (3.6 g, 55.4 mmol) in water/dioxane (30 mL,1:5) at 0° C. After stirring 1 hours, the solution is poured overice-water, the precipitate is collected and washed with water. The solidis dried under vacuum over P₂O₅ (24 hours), dissolved in benzene (30 mL)and heated to reflux slowly over about 4 hours. The benzene is removedto give 2-(3-methoxy-4-methyl-phenyl)vinylisocyanate as a brown oil. Theoil is taken up in o-dichlorobenzene, treated with iodine and heated toreflux for 3.5 hours. The volatiles are removed and the residue is mixedwith 2.5% MeOH/CH₂Cl₂ (10 mL), then allowed to stand overnight at roomtemperature. The resulting solid is collected washed with hexane andether, and dried to give the title compound (2.67 g, 14.1 mmol).

[0538]¹H NMR (CDCl₃, 300 MHz) δ11.80 (bs, 1H), 8.18 (s, 1H), 7.16 (d,1H), 6.86 (s, 1H), 6.51 (d, 1H),3.94 (s, 3H), 2.35 (s, 3H). EI MS,[M.]⁺=189.

[0539] B. 7-bromomethyl-1-chloro-6-methoxy-isoquinoline

[0540] 6-Methoxy-7-methyl-2H-isoquinolin-1-one (2.6 g, 13.7 mmol) isconverted to 6methoxy-7-methyl-2-chloroisoquinoline (2.45 g, 11.8) bythe method described in EXAMPLE 1, Part E. A portion of this material(1.20 g, 5.8 mmol) is converted to7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.8 g, 2.8 mmol) by themethod described in EXAMPLE 1, Part F.

[0541]¹H NMR (CDCl₃, 300 MHz) δ8.30 (s, 1H), 8.22 (d, 1H), 7.49 (d, 1H),7.10 (s, 1H), 4.70 (s, 2H), 4.06 (s, 3H). EI MS, [M.]⁺=285, 287, Clpattern.

[0542] C. [1-(1-Chloro6-methoxyisoquinolin-7ylmethyl)2-oxopyrrolidin-3-(S)-yl]-carbamic acidtert-butyl ester

[0543] Sodium hydride (0.057 g, 1.4 mmol, 60% mineral oil dispersion) issuspended in anhydrous THF (5 mL) and treated with a solution of(2-oxopyrrolidin-3-(S)-yl)carbanic acid tert-butyl ester (0.223 g, 1.1mmol) and 7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.32 g, 1.1mmol in THF/DMF (10 mL, 6:1) at 0° C. The reaction mixture is warmed toambient temperature, stirred for3 hours, quenched by the addition ofsaturated NH₄Cl and diluted with EtOAc. The layers are separated. Theorganic layer is washed with saturated NaCl, dried over Na₂SO₄,filtered, and concentrated to give a white solid. The solid iscollected, washed with a small amount of EtOAc and copious amounts ofEt₂O to yield the title compound (0.18 g, 0.47 mmol).

[0544]¹H NMR (CDCl₃, 300 MHz) δ8.22 (d, 1H), 8.06 (s, 1H), 7.51 (d, 1H),7.11 (s, 1H), 5.20 (bs, 1Il), 4.68 (AB, 2H), 4.23 (m, 1H), 3.98 (s, 3H),3.21 (m, 2H), 2.65 (m, 1H), 1.90 (m, 1H), 1.46 (s, 9H). FAB MS,[M+H]⁺=387.

[0545] D. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-chloro-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0546][1-(1-Chloro-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester (0.15 g, 0.37 mmol) is converted to7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.08 g, 0.15 mmol) by the method described in EXAMPLE 1, Parts I and K.

[0547]¹H NMR (CDCl₃/CD₃OD, 300 MHz) δ8.40 (s, 1H), 8.14 (d, 1H), 7.99(s, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.55 (d, 1H), 7.28(s, 1H), 7.13 (s, 1H), 4.62 (s, 2H), 4.0 (s, 3H), 3.97 (s, 3H), 3.89(dd, 1H), 3.2-3.4 (m, 2H), 2.52 (m, 1H), 2.07 (m, 1H). FAB MS,[M+H]⁺=526.

[0548] E. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-amino-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidehydrochloride

[0549] 7-Methoxynaphthalene-2-sulfonicacid[1-(1-chloro-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.080 g, 0.15 mmol) and phenol (0.430 g, 4.6 mmol) are melted togetherwith stirring at 70° C. for 5 minutes. Ammonium acetate (0.354 g, 4.6mmol) is added and the reaction mixture is heated to 115° C. for about 5hours. Additional ammonium acetate (0.177 g, 2.3 mmol) is added and thereaction is heated for a further 3 hours. The reaction is cooled andpartitioned between 0.5 N NaOH and CH₂Cl₂. The organic layer is driedover Na₂SO₄ and concentrated. The residue is purified by columnchromatography eluting with 5% MeOH/CH₂Cl₂. The product fractions arecollected and concentrated to a small volume, then the residue isacidified with 1N HCl/ether to give a beige solid (0.046 g, 0.095 mmol).

[0550]¹H NMR (CD₃OD, 300 MHz) δ8.38 (s, 1H), 8.05 (s, 1H), 7.88 (d, 1H),7.80 (d, 1H), 7.73 (dd, 1H), 7.44 (d, 1H), 7.32 (d, 1H), 7.30 (s, 1H),7.23 (dd, 1H), 7.07 (d, 1H), 4.53 (AB, 2H), 4.23 (t, 1H), 3.98 (s, 3H),3.89 (s, 3H), 3.30 (m, 2H), 2.22 (m, 1H), 1.89 (m, 1H). FAB MS,[M+H]⁺=478. Elemental analysis calculated with 1.4 mole of H₂O:C=54.96%, H=5.29%, N=9.86%; found C=54.81%, H=5.12%, N=9.71%.

EXAMPLE 11

[0551]7-Methoxynaphthalene-2-sulfonic acid[1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0552] A suspension of 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidein methanol/CH₂Cl₂ (35 mL, 6:1) is treated with THF (5 mL), AcOH (5 mL)and 10% Pd on carbon (0.04 g). The suspension is stirred under anatmosphere of hydrogen for 7 hours. The suspension is filtered, then thefiltrate is concentrated and the residue is purified by RP-HPLC elutingin a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 90% CH₃CN/H₂O (0.1% TFA).The appropriate product fractions are lyophilized to provide the titlecompound as a white solid (0.325g; 0.66 mmol)

[0553]¹H NMR (CD₃OD, 300 MHz) δ9.37 (s, 1H), 8.40 (d, 1H), 8.38 (d, 1H),8.23 (d, 1H), 8.15 (s; 11), 7.93 (d, 1H), 7.85 (d, 1H), 7.77 (dd, 1H),7.66 (s, 1H), 7.35 (s, 1H), 7.27 (dd, 1H), 4.66 (AB, 2H), 4.28 (t, 1H),4.12 (s, 3H), 3.92 (s, 3H), 3.40 (m, 2H), 2.35 (m, 1H), 1.92 (m, 1H).FAB MS, [M+H]⁺492. Elemental analysis calculated with 1.2 mole of H₂O:C=53.66%, H=4.57%, N=6.70%; found C=53.62%, H=4.38%, N=6.67%.

EXAMPLE 12

[0554]4-(2-Chloro-6-nitophenoxy)benzene sulfonic acid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0555][1-(1-Chloro-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester (0.845 g, 2 mmol) is converted to[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester (0.314 g, 0.081 mmol) by the method described inEXAMPLE 10, Part E. A portion of this material (0.285 g, 0.7 mmol) isdeprotected as described in EXAMPLE 1, Part I to yield[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-aminedihydrochloride (0.28 g, 0.78 mmol) and coupled with4-(2-chloro-6-nitophenoxy)benzene sulfonyl chloride (0.35 g, 1 mmol) asdescribed in EXAMPLE 1, Part K. The material obtained upon extractiveworkup and column chromatography is further purified by RP HPLC to givethe title compound (0.04 g, 0.067 mmol).

[0556]¹H NMR (CD₃OD, 300 MHz) δ8.14 (s, 1H), 8.07 (d, 1H), 7.92-7.98 (m,3H), 7.53-7.60 (m, 2H), 7.40 (s, 1H), 7.18 (d, 1H), 7.05 (d, 2H), 4.63(AB, 2H), 4.18 (t, 11H), 4.06 (s, 3H), 3.36 (m, 2H), 2.32 (m, 1H), 1.87(m, 1H). FAB MS, [M+H]⁺=598, 600, Cl pattern. Elemental analysiscalculated with 1.5 mole of H₂O: C=47.13%, H=3.82%, N=9.48%; foundC=47.07%, H=3.66%, N=9.24%.

EXAMPLE 13

[0557]7-Methoxynaphthalene-2-sulfonicacid-[1-(1,6-diamino-isoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0558] A. 3-(3-Acetamido-4-methylphenyl)propenoic acid

[0559] To a solution of 3-acetamido-4-methylbenzaldehyde (14 g, 79 mmol)in pyridine (210 mL) is added piperidine (3.9 mL, 39.4 mmol) and malonicacid (15.26 g, 146.6 mmol). The mixture is heated to 100° C. for 4hours, then stirred at room temperature overnight. The solution isconcentrated in vacuo, then diluted with water. Cold 1 N HCl is added tothe slurry until pH is ca. 4. The solid product (16.178 g, 73.8 mmol) iscollected and washed generously with water. The title compound (16.178g, 73.8 mmol) is then dried over P₂O₅ under vacuum overnight to yield awhite solid.

[0560]¹H NMR (DMSO-d₆, 300 MHz) δ12.30 (bs, 1H), 9.30 (bs, 1H), 7.65 (s,1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.25 (d, 1H), 6.42 (d, 1H), 2.25 (s,3H), 2.09 (s, 3H). El MS [M+H]⁺=220.

[0561] B. 3-(3-Acetylamino-4-methyl-phenyl)acryloyl azide

[0562] To a slurry of3-(3-acetamido4-methylphenyl)propenoic acid (20.11g, 91.7 mmol) in acetone (450 mL) at 0° C. is added triethylamine (12.8mL, 91.8 mmol) followed by dropwise addition of ethyl chloroformate(11.8 mL, 123 mmol) over a 10 minutes period. The resulting yellowslurry is stirred using a mechanical stirrer for 1.5 hours, then asolution of sodium azide (8.94 g, 138 mmol) in water (25 mL) is addedslowly so as to maintain the temperature below 5° C. The thick mixtureis stirred at 0OC for I hours, then the ice bath is removed and thereaction mixture allowed to warm to room temperature. The suspension ispoured over water (800 mL) then filtered. The remaining swlid is washedgenerously with water and dried under vacumn over P₂O₅ overnight to givethe product as a pale yellow solid (21.40 g, 87.6 mmol).

[0563]¹H NMR (CDCl₃, 300 MHz) δ8.10 (s, 1H), 6.71 (d, 1H), 7.22 (m, 2H),6.95 (bs, 1H), 6.38 (d, 1H), 2.29 (s, 3H), 2.21 (s, 3H). El MS[M.]⁺=244.

[0564] C. N-(7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)acetamide

[0565] To a solution of diphenyl ether (250 mL) and tributylamine (11.9mL, 49.9 mmol) at 220-240° C. is added a slurry of3-(3-acetylamino-4-methyl-phenyl)acryloyl azide (12.2 g, 49.9 mmol) indiphenyl ether. After 2 hours, the yellow solution is cooled to roomtemperature and poured over hexane (800 mL). A brown solid precipitatesout and the title product (3.56 g, 16.5 mmol) is obtained as a lightyellow solid by recrystallization from DMF/MeOH.

[0566]¹H NMR (DMSO-d₆, 300 MHz) δ11.0 (bs, 1H), 9.35 (s, 1H), 7.98 (s,1H), 7.89 (s, 1H), 7.05 (m, 1H), 6.45 (d, 1H), 2.32 (s, 3H), 2.12 (s,3H). El MS [M.]⁺=216.

[0567] D. 6-Amino-7-methyl-2H-isoquinolin-1-one

[0568] N-(7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)acetamide (0.366g, 1.69 mmol) and conc. HCl (0.5 mL) is heated to reflux in EtOH (0.84mL). After 6 hours, the mixture is concentrated to dryness, then dilutedwith water and basified using 1 N NaOH until pH is ca. 10. The aqueoussolution is extracted with methylene chloride (4×50 mL) and the organiclayers are combined and washed with brine, dried over MgSO₄, filteredand concentrated. The crude product is purified by column chromatographyeluting with a gradient of 3% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give thetitle product (0.200 g, 1.15 mmol) as a white solid.

[0569]¹H NMR (CDCl₃, 300 MHz) δ8.90 (bs, 1H), 8.06 (s, 1H), 6.90 (m,1H), 6.65 (s, 1H), 6.28 (d, 1H), 4.05 (bs, 2H), 2.20 (s, 3H). EI MS[M.]⁺=174.

[0570] E. 1-Chloro-7-methyl-isoquinolin-6-ylamine

[0571] The title compound is prepared as described in EXAMPLE 1, Part Eusing 6-amino-7-methyl-2H-isoquinolin-1-one as the starting material.The crude product is purified by column chromatography eluting with agradient of 5% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂ to afford the titlecompound as a yellow solid.

[0572]¹H NMR (CDCl₃, 300 MHz) δ8.05 (d, 1H), 8.00 (s, 1H), 7.30 (d, 1H),6.90 (s, 1H), 4.25 (bs, 2H), 2.40 (s, 3H). EI MS [M.]⁺192, 194, Clpattern.

[0573] F. Benzhydrylidene-(1-chloro7-methyl-isoquinolin-6-yl)-amine

[0574] To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine (0.1 g,0.52 mmol) in MeOH (5 mL) at 0° C. is bubbled HCl gas for 1 minute, thenthe solvent is removed in vacuo. The remaining white solid is dilutedwith 1,2dichloroethane and benzophenone imine (0.15 mL, 0.89 mmol) isadded. The resulting suspension is heated to reflux for 48 hours, thencooled to room temperature and concentrated to dryness. The crudematerial is diluted with CH₂Cl₂ and washed with saturated NaHCO₃solution and brine. The organic layer is dried over MgSO₄, filtered andconcentrated. The crude product is purified by column chromatographyusing 10% EtOAc/hexanes as the eluent to afford the title compound(0.159 g, 0.45 mmol) as a yellow oil.

[0575]¹H NMR (CDCl₃, 300 MHz) δ8.05 (m, 2H), 7.80 (m, 2H), 7.45-7.55 (m,4H), 7.20-7.30(m, 3H), 7.10 (m, 2H), 6.75 (s, 1H), 2.50 (s, 3H). FAB MS,[M+H]⁺357, 359, Cl pattern.

[0576] G. Benzhydrylidene-(7-bromomethyl1-chloro-isoquinolin-6-yl)amine

[0577] The title compound is prepared as decribed in EXAMPLE 1, Part Fusing benzhydrylidene-( 1-chloro-7-methyl-isoquinolin-6-yl)-amine as thestarting material. The title compound is obtained as an oil.

[0578]¹H NMR (CDCl₃, 300 MHz) δ8.33 (s, 1H), 8.06 (d, 1H), 7.84 (m, 2H),7.41 (m, 4H), 7.32 (m, 41), 7.20 (d, 1H), 6.66 (s, 1H), 4.79 (s, 2H).FAB MS, [M+H]⁺=435, 437, Cl Br pattern.

[0579] H.{1-[6-(Benzhydrylidene-amino)1-chloro-isoquinolin-7-ylmethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamicacid tert-butyl ester

[0580] The title compound is prepared as described in EXAMPLE 1, Part Husing benzhydrylidene-(7-bromomethyl-1-chloro-isoquinolin-6-yl)-amine inplace of 7-bromomethyl-1-chloroisoquinoline. The crude product ispurified by column chromatography eluting with a gradient of 10%EtOAc/hexanes to 30% EtOAc/hexanes to give the product as a foamy yellowsolid.

[0581]¹H NMR (CDCl₃, 300 MHz) δ8.09 (d, 1H), 8.01 (s, 1H), 7.80 (m, 2H),7.20-7.45 (m, 9H), 6.70 (s, 1H), 5.30 (d, 1H), 4.65 (AB, 2H), 4.21 (m,1H), 3.32 (m, 2H), 2.70 (m, 1H), 1.95 (m, 1H), 1.46 (s, 9H). FAB MS,[M+H]⁺⁼555, 557, Cl pattern.

[0582] I. 7-Methoxynaphthalene-2-sulfonicacid[1-(6-amino1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0583]{1-[6-(Benzhydrylidene-amino)-1-chloro-isoquinolin-7-ylmethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamicacid tert-butyl ester is deprotected as described in EXAMPLE 1, Part Ito yield3-(S)-amino-1-(6-amino-1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride and coupled with 7-methoxynaphthalene-2-sulfonyl chlorideas described in EXAMPLE 1, Part K. The material obtained upon extractiveworkup is purified by column chromatography eluting with a gradient of30% EtOAc/hexanes to 60% EtOAc/hexanes to give the product.

[0584]¹H NMR (CDCl₃, 300 MHz) δ8.34 (s, 1H), 8.02 (d, 1H), 7.93 (s, 1H),7.87 (d, 1H), 7.79 (d, 1H), 7.72 (dd, 1H), 7.29 (dd, 1H), 7.26 (d, 1H),7.25 (s, 1H), 6.77 (s, 1H), 5.61 (bs, 1H), 4.93 (bs, 2H), 4.49 (AB, 2H),3.92 (s, 3H), 3.85 (m, 1H), 3.20 (m, 2H), 2.52 (m, 1H), 2.05 (m, 1H).Ion spray MS, [M+H]⁺=511, 513, Cl pattern.

[0585] J. 7-Methoxynaphthalene-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0586] The title compound is prepared as described in EXAMPLE 2 using7-methoxynaphthalene-2-sulfonicacid[1-(6-amino-1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideas the starting material. No extractive work up is performed. The crudeproduct is purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate fractions are lyophilized toprovide the title compound as a white solid.

[0587]¹H NMR (DMSO-d₆, 300 MHz) δ12.25 (bs, 1H), 8.34-8.38 (d, 2H), 8.24(d, 1H), 7.95 (d, 1H) 7.90-7.93 (d, 2H), 7.68 (dd, 1H), 7.53 (d, 1H),7.38 (d, 1H), 7.30 (dd, 1H), 6.83 (d, 1H), 6.78 (s, 1H), 6.49 (bs, 2H),4.26 (AB, 2H), 4.20 (m, 1H), 3.90 (s, 3H), 3.06 (m, 2H), 2.00 (m, 1H),1.60 (m, 1H). FAB MS, [M+H]⁺=492.

EXAMPLE 14

[0588]6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0589] A. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(6-amino1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0590]{1-[6-(Benzhydrylidene-amino)-1-chloro-isoquinolin-7-ylmethyl]-2-oxopyrrolidin-3-(S)-yl}carbamicacid tert-butyl ester is deprotected as described in EXAMPLE 1, Part Ito yield3-(S)-amino-1-(6-amino1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride and coupled with 6-chloro-benzo[b]thiophene2-sulfonylchloride as described in EXAMPLE 1, Part K. The material obtained uponextractive workup is purified by column chromatography eluting with agradient of 20% EtOAc/hexanes to 60% EtOAc/hexanes to give the product.

[0591]¹H NMR (CDCl₃, 300 MHz) δ8.05 (d, 1H), 8.02 (s, 1H), 7.98 (s, 1H),7.89 (s, 1H), 7.86 (d, 1H), 7.81(d, 1H), 7.44 (dd, 1H), 6.82 (s, 1H),5.40 (d, 1H), 4.90 (bs, 2H), 5.42 (AB, 2H), 3.95 (m, 1H), 330 (m, 2H),2.65 (m, 1H), 2.05 (m, 1H).

[0592] Ion spray MS, [M+H]⁺=521, 523, Cl pattern.

[0593] B. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0594] The title compound is prepared as described in EXAMPLE 2 using6-chloro-benzo[b]thiophene-2-sulfonicacid[1-(6-amino-1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideas the starting material. No extractive work up is performed. The crudeproduct is purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN/H₂O. The appropriate fractions are lyophilizedto provide the title compound as a tan solid.

[0595]¹H NMR (DMSO-d₆, 300 MHz) δ12.05 (bs, 1H), 8.70 (d, 1H), 8.35 (bs,2H), 8.20 (s, 1H), 8.00-8.05 (m, 2H), 7.94 (s, 1H), 7.51 (d, 1H), 7.38(m, 1H), 6.71-6.80 (m, 2H), 6.51 (bs, 2H), 4.30 (m, 3H), 3.20 (m, 2H),2.15 (m, 1H), 1.71 (m, 1H).

[0596] Ion spray MS, [M+H]⁺=502, 504, Cl pattern.

EXAMPLE 15

[0597]7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0598] A. 7-Methyl-1H-quinolin-2-one and 5-methyl-1H-quinolin-2-one

[0599] The title compounds are prepared from m-toluidine and cinnamoylchloride according to the procedure described in Synthesis 1975, 739.The crude solid residue obtained is triturated in Et₂O/hexanes andfiltered to give a mixture of product isomers in a ratio of 1.5:1 of7-methyl-1H-quinolin-2-one to 5-methyl-1H-quinolin-2-one as a beigesolid. Several attempts at purification through fractionalcrystallization in methanol gave only an enriched 2:1 mixture of isomerswhich is used in the subsequent step.

[0600]¹H NMR (DMSO-d₆, 300 MHz) δ7.85 (d, 1H), 7.53 (d, 1H), 7.09 (s,1H), 7.01 (d, 1H), 6.42 (d, 1H), 2.38 (s, 3H) for major isomer(7-methyl); and 67 8.03 (d, 1H), 7.38 (dd, 1H), 7.17 (s, 1H), 7.01 (d,1H), 6.51 (d, 1H), 2.50 (s, 3H) for minor isomer (5-methyl).

[0601] B. 2-Chloro-7-methyl-quinoline and 2-chloro-5-methyl-quinoline

[0602] The title compounds are prepared as described in EXAMPLE 1, PartE using a 2:1 mixture of 7-methyl-1H-quinolin-2-one and5-methyl-1H-quinolin-2-one in place of 7-methyl-2H-isoquinolin-1-one.The crude product is purified by column chromatography eluting with agradient of 5% EtOAc/CH₂Cl₂ to 10% EtOAc/CH₂Cl₂ to afford a 2:1 mixtureof 2-chloro-7-methyl-quinoline to 2-chloro-5-methyl-quinoline as a beigesolid.

[0603]¹H NMR (CDCl₃, 300 MHz) δ8.02 (d, 1H), 7.78 (s, 1H), 7.68 (d, 1H),7.39 (m, 1H), 7.30 (d, 1H), 2.56(s, 3H) for major isomer (7-methyl); andδ8.25 (d, 1H), 7.86 (d, 1H), 7.60 (dd, 1H), 7.39 (m, 2H), 2.65 (s, 3H)for minor isomer (5-methyl).

[0604] C. 7-Bromomethyl-2-chloro-quinoline and5-bromomethyl-2-chloro-quinoline

[0605] The title compounds are prepared as described in EXAMPLE 1, PartF using a 2:1 mixture of 2-chloro-7-methyl-quinoline and2-chloro-5-methyl-quinoline in place of 1-chloro-7-methyl-isoquinoline.The crude mixture of isomers obtained is partially purified bytrituration in EtOAc/hexanes to yield the7-bromomethyl-2-chloro-quinoline as a beige solid (7.4 g, 38%).

[0606]¹H NMR (CDCl₃, 300 MHz) δ8.10 (d, 1H), 8.00 (s, 1H), 7.82 (d, 1H),7.60 (d, 1H), 4.67 (s, 2H).

[0607] An enriched 2:1 mixture of 5-bromomethyl-2-chloro-quinoline to7-bromomethyl-2-chloro-quinoline is isolated as a beige solid (6.8 g)from the concentrated filtrate by fractional recrystallization inEt₂O/hexanes/EtOAc.

[0608]¹H NMR (CDCl₃, 300 MHz) δ8.43 (d, 1H), 8.09 (dd, 1H), 8.03 (m,1H), 7.68 (m, 1H), 7.50 (d, 1H), 4.88 (s, 2H) for major isomer(5-bromomethyl).

[0609] D.[1-(2-Chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0610] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using 7-bromomethyl-2-chloro-quinoline in place of7-bromomethyl-1-chloro-isoquinoline. The crude product is triturated in20% EtOAc/hexanes and filtered to afford the title compound as a beigesolid.

[0611]¹H NMR (CDCl₃, 300 MHz) δ8.10 (d, 1H), 7.83 (s, 1H), 7.80 (d, 1H),7.46 (d, 1H), 7.40 (d, 1H), 5.17 (bs, 1H), 4.68 (AB, 2H), 4.25 (m, 1H),3.26 (m, 2H), 2.64 (m, 1H), 1.88 (m, 1H), 1.46 (s, 9H).

[0612] E. 7-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride

[0613] The title compound is prepared as described in EXAMPLE 1, Part Iusing[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester as the starting material. The title compound isobtained as a white solid.

[0614]¹H NMR (DMSO-d₆, 300 MHz) δ8.75 (bs, 2H), 8.47 (d, 1H), 8.06 (d,1H), 7.86 (s, 1H), 7.61 (d, 1H), 7.58 (d, 1H), 4.69 (AB, 2H), 4.15 (m,1H), 3.35 (m, 2H), 2.43 (m, 1H), 2.04 (m, 1H).

[0615] F. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0616] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride in place of7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)1-chloro-isoquinolinehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as preparedin EXAMPLE 1, Part J. The crude product is triturated in 20%EtOAc/hexanes and filtered to afford the title compound as a whitesolid.

[0617]¹H NMR (CDCl₃, 300 MHz) δ8.38 (s, 1H), 8.08 (d, 1H), 7.92 (d, 1H),7.81 (d, 1H), 7.76 (m, 3H), 7.38 (d, 1H), 7.36 (dd, 1H), 7.30 (dd, 1H),7.25 (m, 1H), 5.44 (s, 1H), 4.61 (s, 2H), 3.96 (s, 3H), 3.78 (m, 1H),3.23 (m, 2H), 2.60 (m, 1H), 2.10 (m, 1H). FAB MS, [M+H]⁺=496, 498, Clpattern. Elemental analysis calculated C=60.54%, H=4.47%, N=8.47%,Cl=7.15%, found C=60.44%, H=4.18%, N=8.45, Cl=7.19%.

[0618] G. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0619] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide isconverted to the title compound when heated at 125° C. as described inEXAMPLE 2. The crude product is partially purified by RP-HPLC eluting ina gradient of 10% CH₃CN/H₂O (0.1% TFA) to 60% CH₃CN/H₂O (0.1% TFA) andthe appropriate product fractions are concentrated in vacuo, filteredand triturated with MeOH as previously described to provide the titlecompound as a white solid.

[0620]¹H NMR (DMSO-d₆, 300 MHz) δ8.62 (bs, 2H), 8.38 (s,1H), 8.31 (d,1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 7.72 (d,1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.32 (dd, 1H), 7.27 (d, 1H), 7.01 (d,1H), 4.50 (AB, 2H), 4.11 (m, 1H), 3.88 (s, 3H), 3.09 (m, 2H), 2.00 (m,1H), 1.58 (m, 1H). Ion spray MS, [M+H]⁺=477. Elemental analysiscalculated C=54.93%, H=4.27%, N=9.49%, found C=54.69%, H=4.24%, N=9.30%.The enantiomeric purity is 81.9% ee as determined by analyticalChiralpak AS RP-HPLC.

EXAMPLE 16

[0621]6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0622] A. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0623] The title compound is prepared in CH₂Cl₂ instead of CH₃CN from7-(3-(S)amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride as described in EXAMPLE 1, Part K using6-chloro-benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 9,Parts A, B and C in place of 7-methoxynaphthalene-2-sulfonyl chloride.The crude product is triturated from EtOAc/hexanes to afford the titlecompound as a beige solid.

[0624]¹H NMR (DMSO-d₆, 300 MHz) δ8.77 (d, 1H), 8.42 (d, 1H), 8.27 (s,1H), 8.07 (s, 1H), 8.04 (d, 1H), 8.02 (d, 1H), 7.75 (s, 1H), 7.58 (d,1H), 7.52 (dd, 1H), 7.48 (d, 1H), 4.55 (AB, 2H), 4.28 (m, 1H), 3.18 (m,2H), 2.18 (m, 1H), 1.71 (m, 1H). Ion spray MS, [M+H]⁺=506, 508, Clpattern.

[0625] B. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0626] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide isconverted to the title compound when heated at 120° C. as described inEXAMPLE 2. The crude product is purified by RP-HPLC eluting in agradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and theappropriate product fractions are lyophilized to provide the titlecompound as a tan solid.

[0627]¹H NMR (DMSO-d₆, 500 MHz) δ8.73 (d, 1H), 8.34 (d, 1H), 8.29 (s,1H), 8.07 (s, 1H), 8.03 (d, 1H), 7.89 (d, 1H), 7.54 (dd, 1H), 7.52 (d,1H), 7.47 (s, 1H), 7.31 (d, 1H), 7.04 (d, 1H), 6.94 (d, 1H), 6.42 (d,1H), 4.53 (AB, 2H), 4.22 (m, 1H), 3.18 (m, 2H), 2.18 (m, 1H), 1.72 (m,1H). FAB MS, [M+H]+=487.

EXAMPLE 17

[0628] Benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0629] A. Benzo[b]thiophene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0630] The title compound is prepared in CHCl₃ instead of CH₃CN from7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride as described in EXAMPLE 1, Part K usingbenzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 8, Part Ain place of 7-methoxynaphthalene-2-sulfonyl chloride. The crude productis triturated from CH₂Cl₂ to afford the title compound as a beige solid.

[0631]¹H NMR (CDCl₃, 300 MHz) δ8.08 (d, 1H), 7.95 (d, 1H), 7.88 (m, 2H),7.99 (d, 1H), 7.76 (s, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 5.62 (s, 1H),4.64 (s, 2H), 3.95 (m, 1H), 3.27 (m, 2H), 2.65 (m, 1H), 2.16 (m, 1H).

[0632] B. Benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0633] Benzo[b]thiophene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide isconverted to the title compound when heated at 130° C. as described inEXAMPLE 2. The crude product is purified by RP-HPLC eluting in agradient of 10% CH₃CN/H₂O (0.1% TFA) to 60% CH₃CN/H₂O (0.1% TFA) and theappropriate product fractions are lyophilized to provide the titlecompound as a tan solid.

[0634]¹H NMR (DMSO-d₆, 500 MHz) δ8.68 (d, 1H), 8.35 (d, 1H), 8.09 (dd,1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.90 (d, 1H), 7.52 (m, 2H), 7.45 (s,1H), 7.32 (d, 1H), 7.04 (d, 1H), 4.53 (AB, 2H), 4.22 (m, 1H), 3.17 (m,2H), 2.18 (m, 1H), 1.72 (m, 1H). Ion spray MS, [M+H]⁺=453.

EXAMPLES 18 AND 19

[0635] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate and 7-methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0636] A. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide

[0637] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.4 g, 0.81 mmol), prepared as in EXAMPLE 15, Part F, is dissolved inDMF (20 mL) and cooled to 0° C. To the solution is added methyl iodide(0.28 g, 2.01 mmol) and sodium hydride (34 mg, 0.85 mmol, 60% mineraloil dispersion). The ice water bath is removed and the mixture isstirred at room temperature for 3 hours. The resulting solution ispoured into a separatory funnel and diluted with EtOAc (100 mL). Theorganic layer is washed with 1N HCl, H₂O and saturated NaCl. The organicphase is then dried over MgSO₄, filtered and concentrated. The cruderesidue is purified by column chromatography eluting with 10%EtOAc/CH₂Cl₂ to give the title compound (0.36 g, 0.71 mmol) as a solid.

[0638]¹H NMR (CDCl₃, 300 MHz) δ8.44 (s, 1H), 8.09 (d, 1H), 7.92 (d, 1H),7.82 (dd, 1H), 7.78 (m, 3H), 7.42 (dd, 1H), 7.40 (d, 1H), 7.28 (dd, 1H),7.26 (s, 1H), 5.00 (m, 1H), 4.62 (AB, 2H), 3.94 (s, 3H), 3.23 (m, 2H),2.84 (s, 3H), 2.33 (m, 1H), 2.03 (m, 1H).

[0639] B. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate and 7-methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0640] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide is converted to the title compounds when heated at 125° C. asdescribed in EXAMPLE 2. The crude mixture of products is purified byRP-HPLC eluting in a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80%CH₃CN/H₂O (0.1% TFA) and the appropriate product fractions arelyophilized to provide 7-methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate as a white solid.

[0641]¹H NMR (DMSO-d₆, 300 MHz) δ8.42 (s, 1H), 8.33 (d, 1H), 8.04 (d,1H), 7.96 (d, 1H), 7.87 (d, 1H), 7.70 (dd, 1H), 7.58 (s, 1H), 7.42 (s,1H), 7.35 (dd, 1H), 7.31 (d, 1H), 7.02 (d, 1H), 4.93 (m, 1H), 4.51 (AB,2H), 3.89 (s, 3H), 3.18 (m, 2H), 2.70 (s, 3H), 2.02 (m, 1H), 1.78 (m,1H). Ion spray MS, [N+H]⁺=491. Elemental analysis calculated with 1.8mol of H₂O cal. C=52.79%, H=4.84%, N=8.80%, found C=52.80%, H=4.35%,N=8.55%.

[0642] 7-Methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amideis also isolated from the reaction mixture as a by-product.

[0643]¹H NMR (DMSO-d₆, 300 MHz) δ8.42 (s, 1H), 8.04 (d, 1H), 7.97 (d,1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 7.58 (s, 1H), 7.35 (dd,1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.45 (d, 1H), 4.90 (m, 1H), 4.40 (AB,2H), 3.89 (s, 3H), 3.15 (m, 2H), 2.71 (s, 3H), 2.01 (m, 1H), 1.76 (m,1H). Ion spray MS, [M+H]⁺=492.

EXAMPLE 20

[0644] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0645] A.[1-(2-Chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0646] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using a 2:1 mixture of5-bromomethyl-2-chloro-quinoline to 7-bromomethyl-2-chloro-quinoline, asprepared in EXAMPLE 15, Part C, in place of7-bromomethyl-1-chloro-isoquinoline. The crude product mixture ispurified by column chromatography eluting with 1% MeOH in 25%EtOAc/CH₂Cl₂ to afford as the major product the title compound as abeige solid.

[0647]¹H NMR (CDCl₃, 300 MHz) δ8.53 (d, 1H), 7.98 (d, 1H), 7.69 (dd,1H), 7.50 (d, 1H), 7.41 (d, 1H), 5.59 (d, 1H), 4.89 (AB, 2H), 4.22 (m,1H), 3.19 (m, 1H), 3.12 (m, 1H), 2.51 (m, 1H), 1.86 (m, 1H), 1.45 (s,9H).

[0648] B. 5-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride

[0649] The title compound is prepared as described in EXAMPLE 1, Part Iusing[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester as the starting material. The title compound isobtained as a white solid.

[0650]¹H NMR (DMSO-d₆, 300 MHz) δ8.63 (d, 1H), 8.59 (bs, 3H), 7.94 (d,1H), 7.81 (m, 1H), 7.65 (m, 2H), 4.89 (s, 2H), 4.08 (m, 1H), 3.24 (m,2H), 2.34 (m, 1H), 1.94 (m, 1H).

[0651] C. 7-Methoxynaphthalene-2-sulfonic acid[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide ps Thetitle compound is prepared in CH₂Cl₂ instead of CH₃CN as described inEXAMPLE 1, Part K using5-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride in place of7-(3-(S)amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinolinehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as preparedin EXAMPLE 1, Part J. The crude product is purified by columnchromatography eluting with 25% EtOAc/CH₂Cl₂ to provide the titlecompound as a light yellow solid.

[0652]¹H NMR (CDCl₃, 300 MHz) δ8.36 (d, 1H), 8.33 (s, 1H), 7.98 (d, 1H),7.91 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.66 (m, 1H), 7.42 (d, 1H),7.35 (d, 1H), 7.30 (dd, 1H), 7.25 (dd, 1H), 5.40 (s, 1H), 4.82 (AB, 2H),3.94 (s, 3H), 3.71 (m, 1H), 3.12 (m, 1H), 3.02 (m, 1H), 2.50 (m, 1H),1.98 (m, 1H). EI MS, [m]⁺=495, 497, Cl pattern. Elemental analysiscalculated C=60.54%, H=4.47%, N=8.47%, Cl=7.15%, found C=59.79%, HH=4.70%, N=7.88, Cl=7.21%.

[0653] D. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0654] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide isconverted to the title compound when heated at 125° C. as described inEXAMPLE 2. The crude product is partially purified by RP-HPLC eluting ina gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) andthe appropriate product fractions are concentrated in vacuo, filtered,triturated with MeOH and then purified further by column chromatographyeluting with a gradient of 1% MeOH/CH₂Cl₂ to 3% MeOH/CH₂Cl₂ to yield thetitle compound as a pale yellow solid.

[0655]¹H NMR (DMSO-d₆, 300 MHz) δ8.48 (d, 1H), 8.37 (s,lH), 8.23 (d,1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.72 (m, 1H), 7.69 (d, 1H), 7.60 (d,1H), 7.55 (s, 1H), 7.33 (m, 2H), 7.07 (d, 1H), 4.71 (AB, 2H), 4.11 (m,1H), 3.88 (s, 3H), 3.00 (m, 2H), 1.94 (m, 1H), 1.48 (m, 1H). FAB MS,[M+H]⁺=477. Elemental analysis calculated with 2.5 mol of H₂O cal.C=50.98%, H=4.14%, N=8.38%, found C=50.96%, H=4.14%, N=8.38%. Theenantiomeric purity is 84.5% ee as determined by analytical Chiralpak ASRP-HPLC.

EXAMPLES 21 AND 22

[0656] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate and 7-methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-5-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0657] A. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-5-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-methylamide

[0658] The title compound is prepared as in EXAMPLES 18 AND 19, Part Ausing 7-methoxynaphthalene-2--sulfonicacid[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide asthe starting material. The crude product is purified by columnchromatography eluting with 50% EtOAc/hexanes to afford the titlecompound as a white solid.

[0659]¹H NMR (CDCl₃, 300 MHz) δ8.42 (s, 1H), 8.38 (s, 1H), 7.97 (d, 1H),7.91 (d, 1H), 7.78 (m, 2H), 7.66 (dd, 1H), 7.43 (d, 1H), 7.30 (d, 1H),7.25 (m, 2H), 4.92 (m, 1H), 4.80 (AB, 2H), 3.92 (s, 3H), 3.08 (m, 2H),2.74 (s, 3H), 2.22 (m, 1H), 1.80 (m, 1H).

[0660] B. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate and 7-methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-5-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0661] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide is converted to the title compounds when heated at 120° C. asdescribed in EXAMPLE 2. The crude product is purified by RP-HPLC elutingin a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA)and the appropriate product fractions are lyophilized to provide7-methoxynaphthalene-2-sulfonic acid[1-(2-aminoquinolin5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methyl amidetrifluoroacetate as a white solid.

[0662]¹H NMR (DMSO-d₆, 300 MHz) δ8.46 (d, 1H), 8.39 (s, 1H), 8.03 (d,1H), 7.96 (d, 1H), 7.70 (m, 2H), 7.60 (d, 1H), 7.58 (s, 1H), 7.36 (dd,1H), 7.34 (d, 1H), 7.06 (d, 1H), 4.90 (m, 1H), 4.71 (AB, 2H), 3.89 (s,3H), 3.11 (m, 1H), 3.00 (m, 1H), 2.63 (s, 3H), 1.95 (m, 1H), 1.68 (m,1H). FAB MS, [M+H]⁺=491. 7-Methoxynaphthalene-2-sulfonic acidmethyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-5-ylmethyl)-pyrrolidin-3-(S)-yl]-amideis also isolated from the reaction mixture as a by-product.

[0663]¹H NMR (DMSO-d₆, 300 MHz) δ8.39 (s, 1H), 8.04 (d, 1H), 7.98(d,1H), 7.94 (d, 1H), 7.68 (d, 1H), 7.57 (s, 1H), 7.42 (m, 1H), 7.34(dd, 1H), 7.25 (d, 1H), 7.05 (d, 1H), 6.46 (d, 1H), 4.88 (m, 1H), 4.60(AB, 2H), 3.89 (s, 3H), 3.08 (m, 1H), 2.97 (m, 1H), 2.63 (s, 3H), 1.96(m, 11i), 1.65 (m, 1H). FAB MS, [M+H]⁺=492.

EXAMPLES 23 AND 24

[0664]7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide and7-methoxynaphthalene-2-sulfonicacid[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0665] A. 6-Methyl-1H-quinolin-2-one

[0666] The title compound is prepared from p-toluidine and cinnamoylchloride according to the procedure described in Synthesis 1975, 739.The crude product obtained is triturated in Et₂O/hexanes and filtered togive the title compound as a beige solid which is used in the subsequentstep.

[0667]¹H NMR (DMSO-d₆, 300 MHz) δ11.60 (bs, 1H), 7.82 (d, 1H), 7.41 (s,111), 7.30 (d, 1H), 7.18 (d, 1H), 6.45 (d, 1H), 2.30 (s, 3H).

[0668] B. 2-Chloro-6-methyl-quinoline

[0669] The title compound is prepared as described in EXAMPLE 1, Part Eusing 6-methyl-1H-quinolin-2-one in place of7-methyl-2H-isoquinolin-1-one. The crude product precipitated out duringneutralization of the aqueous workup and the solid is filtered anddried. The crude product is recrystallized in MeOH to afford the titlecompound as a beige solid.

[0670]¹H NMR (CDCl₃, 300 MHz) δ8.02 (d, 1H), 7.92 (d, 1H), 7.60 (s, 1H),7.58 (d, 1H), 7.33 (d, 1H), 2.53 (s, 3H).

[0671] C. 6-Bromomethyl-2-chloro-quinoline

[0672] The title compound is prepared as described in EXAMPLE 1, Part Fusing 2-chloro-6methyl-quinoline in place of1-chloro-7-methyl-isoquinoline. The crude residue obtained isrecrystallized from 50% EtOAc/hexanes to yield 7.4 g (38%) of the6-bromomethyl-2-chloro-quinoline as a beige solid.

[0673]¹H NMR (CDCl₃, 300 MHz) δ8.08 (d, 1H), 8.02 (d, 1H), 7.83 (s, 1H),7.77 (dd, 1H), 7.40 (d, 1H), 4.65 (s, 2H). EI MS, [M]⁺=256, 258, Clpattern.

[0674] D.[1-(2-Chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0675] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using 6-bromomethyl-2-chloro-quinoline in place of7-bromomethyl-1-chloro-isoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 2% MeOH/CH₂Cl₂ to 4%MeOH/CH₂Cl₂ to afford the title compound as a beige solid.

[0676]¹H NMR (CDCl₃, 300 MHz) δ8.08 (d, 1H), 8.00 (d, 1H), 7.69 (s, 1H),7.61 (dd, 1H), 7.40 (d, 1H), 5.23 (bs, 1H), 4.67 (AB, 2H), 4.25 (m, 1H),3.26 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.46 (s, 9H).

[0677] E. 6-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride

[0678] The title compound is prepared as described in EXAMPLE 1, Part Iusing[1-(2-chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester as the starting material. The title compound isobtained as a white solid.

[0679]¹H NMR (DMSO-d₆, 300 MHz) δ8.74 (bs, 3H), 8.48 (d, 1H), 8.00 (s,1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.60 (d, 1H), 4.64 (AB, 2H), 4.11 (m,1H), 3.35 (m, 2H), 2.42 (m, 1H), 2.09 (m, 1H).

[0680] F. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0681] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using6-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinolinehydrochloride as the starting material and7-methoxynaphthalene-2-sulfonyl chloride. The crude product istriturated in CH₂Cl₂ and filtered to provide the title compound as awhite solid.

[0682]¹H NMR (CDCl₃, 300 MHz) δ8.36 (s, 1H), 8.03 (d, 1H), 7.97 (d, 1H),7.91 (d, 1H), 7.80 (d, 1H), 7.75 (dd, 1H), 7.60 (s, 1H), 7.51 (dd, 1H),7.37 (d, 1H), 7.29 (dd, 1H), 7.25 (dd, 1H), 5.43 (s, 1H), 4.58 (AB, 2H),3.94 (s, 3H), 3.76 (m, 1H), 3.22 (m, 2H), 2.59 (m, 1H), 2.09 (m, 1H).FAB MS, [M+H]⁺=496, 498, Cl pattern. Elemental analysis calculatedC=60.54%, H=4.47%, N=8.47%, Cl=7.15%, found C=60.43%, H=4.17%, N=8.37,Cl=7.06%.

[0683] G. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin6-ylmethyl)-2-oxopyrrolidin-3S)-yl]-amide and7-methoxynaphthalene-2-sulfonicacid[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0684] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide is converted to the title compounds when heated at 130° C. asdescribed in EXAMPLE 2. The crude mixture of products is purified byRP-HPLC eluting in a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 60%CH₃CN/H₂O (0.1% TFA) and the appropriate product fractions areconcentrated in vacuo and then purified further by column chromatographyeluting with 5% MeOH/CH₂Cl₂ to yield 7-methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as atan solid.

[0685]¹H NMR (DMSO-d₆, 300 MHz) δ8.38 (s, 1H), 8.23 (d, 1H), 8.03 (d,1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.55 (s, 1H), 7.41 (s,1H), 7.38 (d, 1H), 7.32 (dd, 1H), 7.25 (d, 1H), 6.73 (d, 1H), 6.43 (bs,2H), 4.37 (AB, 2H), 4.10 (m, 1H), 3.88 (s, 3H), 3.04 (m, 2H), 1.96 (m,1H), 1.51 (m, 1H). FAB MS, [M+H]⁺=477. Elemental analysis calculatedwith 0.6 mol of H₂O cal. C=61.58%, H=5.22%, N=11.49%, found C=61.59%,H=5.08%, N=11.14%. The enantiomeric purity is 87.0% ee as determined byanalytical Chiralpak AS RP-HPLC.

[0686] 7-Methoxynaphthalene-2-sulfonicacid[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-amideis also isolated from the reaction mixture as a minor by-product.

[0687]¹H NMR (DMSO-d₆, 300 MHz) δ11.70 (bs, 1H), 8.37 (s, 1H), 8.21 (d,1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.82 (d, 1H), 7.69 (d, 1H), 7.56 (s,1H), 7.45 (s, 1H), 7.32 (m, 2H), 7.25 (m, 1H), 6.47 (d, 1H), 4.35 (s,2H), 4.12 (m, 1H), 3.89 (s, 3H), 3.06 (m, 2H), 1.97 (m, 1H), 1.53 (m,1H). FAB MS, [M+H]⁺=478.

EXAMPLE 25

[0688]7-Methoxynaphthalene-2-sulfonic acid[1-(1H-benzoimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0689] A. [1-(4-Nitrobenzyl)2-oxopyrrolidin-3-(S)-yl]-carbamic acidtert-butyl ester

[0690] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using 4-nitrobenzyl bromide in place of7-bromomethyl-1-chloro-isoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 10% EtOAc/CH₂Cl₂ to 25%EtOAc/CH₂Cl₂ to afford the title compound as a yellow solid.

[0691]¹H NMR (CDCl₃, 300 MHz) δ8.20 (d, 2H), 7.43 (d, 2H), 5.18 (bs,1H), 4.58 (AB, 2H), 4.22 (m, 1H), 3.26 (m, 2H), 2.65 (m, 1H), 1.93 (m,1H), 1.46 (s, 9H).

[0692] B. 3-(S)-Amino-1-(4-nitrobenzyl)pyrrolidin-2-one hydrochloride

[0693] The title compound is prepared as described in EXAMPLE 1, Part Iusing [1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acidtert-butyl ester as the starting material. The title compound isobtained as a white solid.

[0694]¹H NMR (DMSO-d₆, 300 MHz) δ8.65 (bs, 3H), 8.22 (d, 2H), 7.57 (d,2H), 4.59 (AB,2H), 4.10 (m, 1H), 3.32 (m, 2H), 2.40 (m, 1H), 2.03 (m,1H).

[0695] C.2,2,2-Trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide

[0696] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using3-(S)-amino-1-(4-nitrobenzyl)-pyrrolidin-2-one hydrochloride as thestarting material and trifluoroacetic anhydride in place of7-methoxynaphthalene-2-sulfonyl chloride. The crude product isconcentrated in vacuo and used as is in the subsequent step.

[0697]¹H NMR (CDCl₃, 300 MHz) δ8.24 (d, 2H), 7.43 (d, 2H), 7.25 (bs,1H), 4.60 (AB, 2H), 4.44 (m, 1H), 3.35 (m, 2H), 2.80 (m, 1H), 2.01 (m,1H).

[0698] D.N-[1-(4-Acetylamino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide

[0699] To a solution of2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-acetamide(0.75 g, 2.27 mmol) in AcOH (12 mL) is added acetic anhydride (1 mL) anda catalytic amount of 10% palladium on activated carbon. Theheterogenous mixture is hydrogenated at room temperature on a Parrapparatus under 70 p.s.i. of H₂. After 4.5 h, the reaction mixture isfiltered through a pad of Celite, washed with CH₂Cl₂ and then MeOH. Thecrude product is concentrated in vacuo to yield 1.2 g of crudeN-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamideas a residue (wet with HOAc). A solution of the crudeN-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide(1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0° C. and aceticanhydride (1 mL) is added. The resulting mixture is treated with acatalytic amount of NaNO₂, followed by the dropwise addition of fumingHNO₃ (3.8 mL). The reaction mixture is stirred at 0° C. for 1.5 hours,then at room temperature for 1.5 hours. Upon re-cooling to 0° C., amixture of ice/ice water is added slowly with stirring. The mixture isdiluted further with water and extracted with EtOAc (3×50 mL). Thecombined organic layers are washed twice with water. The organic phaseis dried over anhydrous MgSO₄, filtered and concentrated. The crudeproduct is purified by column chromatography eluting with a gradient of25% EtOAc/CH₂Cl₂ to 50% EtOAc/CH₂Cl₂ to provide the title compound (0.65g, 1.67 mmol) as a beige solid.

[0700]¹H NMR (CDCl₃, 300 MHz) δ10.27 (s, 1H), 8.77 (d, 1H), 8.08 (s,1H), 7.54 (m, 1H), 7.40 (bs, 1H), 4.51 (AB, 2H), 4.46 (m, 1H), 3.34 (m,2H), 2.78 (m, 1H), 2.31 (s, 3H), 1.98 (m, 1H) for the major component ofa mixture of rotamers.

[0701] E. 3-(S)-Amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one

[0702] To a solution ofN-[1-(4-acetylamino-3-nitrobenzyl)2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide(0.65 g, 1.67 mmol) in EtOH (4 mL) is added 1 N NaOH (6 mL) solution.The yellow mixture is heated at 50° C. for 3 hours as a brown solutionresulted. The reaction mixture is allowed to cool and then concentratedin vacuo. The crude residue is diluted with water and 1 N NaOH 10 mL)and the aqueous phase is extracted with CHCl₃ (4×50 mL). The combinedorganic layers are dried over anhydrous Na₂SO₄, filtered andconcentrated to give the title compound (0.22 g, 0.88 mmol) as a yellowsolid which is used as is in the subsequent step.

[0703]¹H NMR (CDCl₃, 300 MHz) δ7.98 (s, 1H), 7.30 (dd, 1H), 6.79 (d,1H), 6.12 (bs, 2H), 4.36 (AB, 2H), 3.67 (m, 1H), 3.19 (m, 2H), 2.43 (m,1H), 1.71 (m, 1H).

[0704] F. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0705] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using3-(S)-amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one in place of7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinolinehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as preparedin EXAMPLE 1, Part J. The crude product is purified by columnchromatography eluting with a gradient of 20% EtOAc/CH₂Cl₂ to 50%EtOAc/CH₂Cl₂ to afford the title compound as a pale yellow solid.

[0706]¹H NMR (CDCl₃, 300 MHz) δ8.37 (s, 1H), 7.94 (s, 1H), 7.92 (d, 1H),7.82 (d, 1H), 7.75 (dd, 1H), 7.30 (dd, 1H), 7.25 (dd, 1H), 7.19 (dd,1H), 6.77 (d, 1H), 6.12 (bs, 2H), 5.38 (bs, 1H), 4.30 (AB, 2H), 3.94 (s,3H), 3.73 (m, 1H), 3.18 (m, 2H), 2.58 (m, 1H), 2.05 (m, 1H).

[0707] G. 7-Methoxynaphthalene-2-sulfonicacid[1-(1H-benzoimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-y1-amidetrifluoroacetate

[0708] To a solution of 7-methoxynaphthalene-2-sulfonicacid[1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.38 g,0.82 mmol) in 88% HCO₂H (15 mL) is added a catalytic amount of 10%palladium on activated carbon. The heterogenous mixture is hydrogenatedat room temperature on a Parr apparatus under 70 p.s.i. of H₂ for 1hour. The reaction mixture is filtered through a pad of Celite, washedwith EtOAc and MeOH, and the filtrate is concentrated in vacuo. Thecrude product is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound (0.17 g,0.30 mmol) as a white solid.

[0709]¹H NMR (DMSO-d₆, 300 MHz) δ9.38 (bs, 1H), 8.38 (s, 1H), 8.25 (d,1H), 8.03 (d, 1H), 7.95 (d, 1H), 7.78 (d, 1H), 7.72 (dd, 1H), 7.66 (bs,1H), 7.56 (s, 1H), 7.35 (d, 1H), 7.32 (dd, 1H), 4.48 (AB, 2H), 4.09 (m,1H), 3.88 (s, 3H), 3.06 (m, 2H), 1.96 (m, 1H), 1.53 (m, 1H). FAB MS,[M+H]⁺=451. Elemental analysis calculated with 1.2 mol H₂O cal.C=51.19%, H=4.37%, N=9.55%, found C=51.19%, H=3.95%, N=9.36%.

EXAMPLE 26

[0710] 7-Methoxynaphthalene-2-sulfonicacid[2-(1H-benzoimidazol-5-ylethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0711] A. Boc-L-Asp(H)—OBn.

[0712] Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in THF (50 mL) andcooled to −10° C. The solution is treated with N-methylmorpholine (4.9g, 48.7 mmol) and stirred for 5 minutes. To the solution is addeddropwise isobutyl chloroformate (6.3 g, 46.4 mmol). After the additionis completed, the mixture is stirred for 1 minute and then filteredthrough a pad of Celite. The filtrate is cooled to −10° C. To thesolution is added sodium borohydride (2.63 g, 70 mmol) which ispredissolved in water (50 mL). The resulting solution is stirred for 2minutes. The solution is poured into a separatory funnel and dilutedwith EtOAc (800 mL). The organic layer is washed with water andsaturated NaCl. The organic layer is dried over MgSO₄, filtered andconcentrated in vacuo. The residue is added to a solution of oxalylchloride (30 mL, 60 mmol, 2M solution in CH₂Cl₂), and methyl sulfoxide(7.25 g, 92.8 mmol) in CH₂Cl₂(250 mL) at −78° C. The mixture is stirredat −78° C. for 40 minutes, then triethylamine (14 g, 140 mmol) is added.The reaction mixture is stirred at −78° C. for 1 hour and then isstirred at room temperature for 30 minutes. The solution is poured intoa 20% citric acid/water (200 mL) solution. The resulting mixture ispoured into a separatory funnel and the layers are separated. Theorganic layer is washed with water and saturated NaCl. The organic phaseis dried over MgSO₄, filtered and concentrated. The crude residue ispurified by column chromatography eluting with a gradient of 10%EtOAc/hexanes to 30% EtOAc/hexanes to give the title compound (12.0 g,39 mmol) as an oil.

[0713]¹H NMR (CDCl₃, 300 MHz) δ9.68 (s, 1H), 7.32 (m, 4H), 5.42 (bs,1H), 5.16 (s, 2H), 4.62 (m, 2H), 3.05 (ddd, 2H), 1.40 (s, 9H).

[0714] B.{1-[2-(4-Nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamic acidtert-butyl ester

[0715] To a solution of Boc-L-Asp(H)—OBn (3.3 g, 10.7 mmol) dissolved inmethanol (50 mL) is added 4 Å molecular sieves, 4-nitrophemethylaminehydrochloride (4.35 g, 21.5 mmol) and triethylamine (2.25 g, 22.2 mmol).The solution is stirred at room temperature for 45 minutes and then themixture is treated with sodium cyanoborohydride (0.72 g, 11.5 mmol). Thereaction mixture is stirred at room temperature for 16 hours. After thistime, 1 N NaOH (10 mL) followed by water (25 mL) is added. The resultingmixture is stirred for 30 minutes and then concentrated in vacuo to asmaller volume. The solution is diluted with EtOAc (250 mL), filteredthrough a pad of Celite and washed with water and EtOAc. The solution ispoured into a separatory funnel and the layers are separated. Theaqueous layer is extracted with EtOAc. The combined organic layers arewashed with 1N HCl, H₂, saturated NaHCO₃ solution and saturated NaCl.The organic phase is dried over MgSO₄, filtered and concentrated. Thecrude residue is purified by column chromatography eluting with 50%EtOAc/CH₂Cl₂ to afford the title compound (1.46 g, 4.18 mmol) as a paleyellow solid.

[0716]¹H NMR (CDCl₃, 300 MHz) δ8.17 (d, 2H), 7.39 (d, 2H), 5.12 (bs,1H), 4.09 (m, 1H), 3.63 (m, 2H), 3.25 (m, 2H), 2.99 (t, 2H), 2.62 (m,1H), 1.83 (m, 1H), 1.44 (s, 9H).

[0717] C. 3-(S)-Amino-1-[2-(4-nitrophenyl)-ethyl]-pyrrolidin-2-onehydrochloride

[0718] The title compound is prepared as described in EXAMPLE 1, Part Iusing {1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamicacid tert-butyl ester as the starting material. The title compound isobtained as a beige solid.

[0719]¹H NMR (CDCl₃/CD₃OD, 300 MHz) δ8.77 (bs, 1H), 8.72 (bs, 1H), 8.16(d, 2H), 7.45 (d, 2H), 4.15 (m, 1H), 3.59 (t, 2H), 3.38 (m, 2H), 2.98(t, 2H), 2.58 (m, 1H), 2.37 (m, 1H).

[0720] D.2,2,2-Trifluoro-N-{1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-acetamide

[0721] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using3-(S)-amino-1-[2-(4-nitrophenyl)-ethyl]-pyrrolidin-2-one hydrochlorideas the starting material and trifluoroacetic anhydride in place of7-methoxynaphthalene-2-sulfonyl chloride. The crude product isconcentrated in vacuo and used as is in the subsequent step.

[0722]¹H NMR (CDCl₃, 300 MHz) δ8.17 (d, 2H), 8.15 (bs, 1H), 7.39 (d,2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.55 (m, 1H), 3.34 (m, 2H), 2.99 (t,2H), 2.68 (m, 1H), 1.96 (m, 1H).

[0723] E.N-{-[2-(4-Acetylamino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide

[0724] The title compound is prepared as described in EXAMPLE 25, Part Dusing2,2,2-trifluoro-N-{1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-acetamideas the starting material. The crude intermediate is concentrated invacuo to yieldN-{1-[2-(4-acetylamino-phenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamideas a residue (wet with HOAc) which is also used directly in thenitration step. The nitric acid reaction mixture is allowed to warm toroom temperature and stirred for 18 hours. The crude product is purifiedby column chromatography eluting with a gradient of 25% EtOAc/CH₂Cl₂ to50% EtOAc/CH₂Cl₂ to provide the title compound as a solid.

[0725]¹H NMR (CDCl₃, 300 MHz) δ10.24 (s, 1H), 8.70 (d, 1H), 7.98 (bs,1H), 7.40 (d, 1H), 7.26 (bs, 1H), 4.43 (m, 1H), 3.58 (m, 2H), 3.38 (m,2H), 2.94 (m, 2H), 2.66 (m, 1H), 2.06 (s, 3H), 1.98 (m, 1H) for themajor component of a mixture of rotamers.

[0726] F.3-(S)-Amino-1-[2-(4-amino-3-nitrophenyl)ethyl]-pyrrolidin-2-one

[0727] The title compound is prepared as described in EXAMPLE 25, Part FusingN-{1-[2-(4-acetylamino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamideas the starting material. The reaction mixture is stirred at roomtemperature for 18 hours. After similar workup, the organic phase isconcentrated in vacuo to give the title compound as a yellow solid whichis used as is in the subsequent step.

[0728]¹H NMR (CDCl₃, 300 MHz) δ7.90 (s, 1H), 7.25 (d, 1H), 6.80 (d, 1H),6.24 (bs, 1H), 3.48 (m, 3H), 3.26 (m, 2H), 2.77 (t, 2H), 2.40 (m, 1H),2.25 (bs, 3H), 1.69 (m, 1H).

[0729] G. 7-Methoxynaphthalene-2-sulfonicacid{1-[2-(4-amino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-amide

[0730] The title compound is prepared in CH₂Cl₂ instead of CH₃CN asdescribed in EXAMPLE 1, Part K using3-(S)-amino-1-[2-(4-amino-3-nitrophenyl)-ethyl]-pyrrolidin-2-one inplace of7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinolinehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as preparedin EXAMPLE 1, Part J. After similar workup, the organic phase isconcentrated in vacuo to afford the title compound as a pale yellowsolid which is used as is in the subsequent step.

[0731]¹H NMR (CDCl₃, 300 MHz) δ8.36 (s, 1H), 7.87 (d, 1H), 7.83 (s, 1H),7.77 (d, 1H), 7.72 (dd, 1H), 7.27 (dd, 1H), 7.22 (s, 1H), 7.13 (dd, 1H),6.68 (d, 1H), 6.04 (bs, 2H), 5.33 (bs, 1H), 3.93 (s, 3H), 3.68 (m, 1H),3.44 (m, 2H), 3.20 (m, 2H), 2.68 (t, 2H), 2.49 (m, 1H), 1.98 (m, 1H).

[0732] H. 7-Methoxynaphthalene-2-sulfonicacid{1-[2-(1H-benzoimidazol-5-yl)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0733] 7-Methoxynaphthalene-2-sulfonicacid{1-[2-(4-amino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-amideis converted to the title compound as described in EXAMPLE 25, Part H.The crude product is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 60% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0734]¹H NMR (DMSO-d₆, 300 MHz) δ9.38 (bs, 1H), 8.35 (s, 1H), 8.13 (d,1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.73 (d, 1H), 7.69 (s, 1H), 7.65 (d,1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 3.90 (m, 1H), 3.88 (s,3H), 3.39 (m, 2H), 3.11 (m, 2H), 2.88 (t, 2H), 1.94 (m, 1H), 1.47 (m,1H). FAB MS, [M+H] 465. Elemental analysis calculated with 1.4 mol H₂Ocal. C=51.68%, H=4.65%, N=9.27%, found C=51.68%, H=4.25%, N=8.93%.

EXAMPLE 27

[0735]7-Methoxynaphthalene-2-sulfonic acidacetyl-[2-oxo-1-(2-pyrrolo[3,2-b]pyridin-1-ylethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate

[0736] A. 1H-Pyrrolo[3,2-c]pyridine

[0737] The title compound is prepared from 3-picoline-N-oxide accordingto the procedure described in Tetrahedron 1993, 2885. The crude productobtained is dissolved in EtOH and decolorizing carbon is added. Themixture is filtered through a large column of SiO₂ gel eluting with EtOHto provide the title compound as a beige solid.

[0738]¹H NMR (CDCl₃, 300 MHz) δ10.92 (bs, 1H), 8.98 (s, 1H), 8.31 (d,1H), 7.36 (d, 1H), 7.32 (d, 1H), 6.66 (d, 1H).

[0739] B. Pyrrolo[3,2-c]pyridin1-yl-acetic acid tert-butyl ester

[0740] The title compound is prepared from 1H-pyrrolo[3,2-c]pyridine asdescribed in EXAMPLES 18 and 19, Part A using tert-butyl bromoacetate inplace of methyl iodide. The crude product is purified by columnchromatography eluting with a gradient of 3% MeOH/CH₂Cl₂ to 6%MeOH/CH₂Cl₂ to give the title compound as an oil.

[0741]¹H NMR (CDCl₃, 300 MHz) δ8.93 (s, 1H), 8.34 (d, 1H), 7.18 (d, 1H),7.12 (d, 1H), 6.65 (d, 1H), 4.75 (s, 2H), 1.45 (s, 9H).

[0742] C. Pyrrolo[3,2-c]pyridin-1-yl-acetic acid

[0743] To a solution of pyrrolo[3,2-c]pyridin-1-yl-acetic acidtert-butyl ester (0.44 g, 1.89 mmol) in CH₂Cl₂ (10 mL) at 0° C. is addedtrifluoroacetic acid (1 mL). After 15 minutes, the solution is allowedto warm to room temperature and stirred for 18 hours. The reactionmixture is concentrated in vacuo and then azeotroped with toluene togive 0.5 g of the title compound as a residue (wet with excess TFA)which is used as is in the subsequent step

[0744]¹H NMR (CDCl₃+CD₃OC, 300 MHz) δ9.09 (s, 1H), 8.34 (d, 1H), 7.91(d, 1H), 7.71 (d, 1H), 7.08 (d, 1H), 5.18 (s, 2H).

[0745] D.2-(S)-Benzyloxycarbonylamino4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyricacid methyl ester

[0746] Pyrrolo[3,2-c]pyridin-1-yl-acetic acid (0.50 g, 1.89 mmol),2-(S)-benzyloxycarbonylamino-4-amino-butyric acid methyl estertrifluoroacetate (0.93 g, 2.45 mmol), 4-methylmorpholine (0.75 g, 7.41mmol), and 1-hydroxybenzotriazole hydrate (0.36 g, 2.65 mmol) aredissolved in DMF (11 mL) and the resulting mixture is cooled to 0° C.1-(3-Dimethylaminopropyl)-3-ethylcarbodiiimide hydrochloride (0.80 g,4.17 mmol) is added to the solution. The ice bath is removed and thereaction mixture is stirred at room temperature. After 18 hours, thesolution is diluted with a saturated solution of NH₄Cl and extractedtwice with EtOAc. The combined organic layers are washed with H₂,saturated NaHCO₃ and saturated NaCl. The organic phase is dried overMgSO₄, filtered and concentrated in vacuo. The crude product is purifiedby column chromatography in a gradient of 3% MeOH/CH₂Cl₂ to 10%MeOH/CH₂Cl₂ to afford the title compound (0.33 g, 0.78 mmol) as a solid.

[0747]¹NMR (CDCl₃, 300 MHz) δ8.95 (s, 1H), 8.35 (d, 1H), 7.34 (m, 3H),7.27 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H), 6.44 (bs, 1H), 5.45 (d, 1H),4.93 (s, 2H), 4.78 (s, 2H), 4.08 (m, 1H), 3.69 (s, 3H), 3.67 m, 1H),2.90 (m, 1H), 2.03 (m, 1H), 1.58 (m, 1H).

[0748] E. 7-Methoxynaphthalene-2-sulfonic acidacetyl-[2-oxo-1-(2-pyrrolo[3,2-b]pyridin-1-ylethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0749] To a solution of2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyricacid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirredat room temperature for 4 hours and then concentrated in vacuo. Theresidue is suspended in EtOAc (10 mL), treated with 10 drops of H₂O, 5drops of 1 N NaOH and further quenched with saturated NH₄Cl solution.The mixture is concentrated in vacuo to about ½ volume, partitionedbetween EtOAc and 10% Na₂CO₃ solution and the layers are separated. Theaqueous layer is extracted with EtOAc. The combined organic phases arewashed with saturated NaCl, dried over MgSO₄, filtered and concentratedin vacuo. The crude product obtained is partially purified by columnchromatography in a gradient of 2% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂ toafford[2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamicacid benzyl ester. FAB MS, [M+H]⁺=379. To a solution of this crude[2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamicacid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalyticamount of 10% palladium on activated carbon. The heterogenous mixture isstirred at room temperature under a balloon of H₂ for 18 hours. Thereaction mixture is filtered through a pad of Celite and washed withMeOH (3×). The crude product is concentrated in vacuo and thenazeotroped with toluene to give3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)pyrrolidin-2-oneacetate as a residue (wet with excess HOAc). FAB MS, [M+H]⁺=245. Thetitle compound is prepared in CH₂Cl₂ instead of CH₃CN as described inEXAMPLE 1, Part K using the above3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-oneacetate in place of7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinolinehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as preparedin EXAMPLE 1, Part J. The crude product is partially purified by columnchromatography eluting in a gradient of 3% MeOH/CH₂Cl₂ to 5%MeOH/CH₂Cl₂. The residue obtained is further purified by RP-HPLC elutingin a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA)and the appropriate product fractions are lyophilized to provide thetitle compound as a white solid.

[0750]¹H NMR (DMSO-d₆, 300 MHz) δ9.24 (s, 1H), 8.58 (s, 1H), 8.48 (d,1H), 8.20 (d, 1H), 8.08 (d, 1H), 8.00 (d, 1H), 7.98 (s, 1H), 7.75 (dd,1H), 7.61 (s, 1H), 7.42 (dd, 1H), 7.03 (d, 1H), 4.87 (m, 1I, 4.56 (m,2H), 3.90 (s, 3H), 3.63 (m, 2H), 3.30 (m, 2H), 2.27 (m, 1H), 2.15 (s,3H), 2.04 (m, 1H). FAB MS, [M+H]⁺=507.

EXAMPLE 28

[0751] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-quinazolin-6-yl-methyl)-2-oxopyrrolidin-3-(S)yl]-methylamidetrifluoroacetate

[0752] A. 6Methyl-3H-quinazolin-4-one

[0753] Sodium hydride (2.6 g, 65 mmol, 60% mineral oil dispersion) isadded to dioxane (100 mL) at 0° C. To the solution is added2-amino-5-methyl benzoic acid (7.6 g, 50 mmol) followed by[3-(dimethylamino)-2-azoprop2-en-1-ylidene]dimethyl ammonium chloride(9.9 g, 60 mmol). After addition, the solution is heated to reflux.Refluxing is continued for 16 hours. The reaction mixture is cooled toambient temperature and methanol (3 mL) is added followed by AcOH (10mL). The solution is then refluxed for 3 hours. The solution is cooledto ambient temperatures. The solution is concentrated. The resultingsolid is diluted with water (60 mL). The pH of the resulting solution isadjusted to 7. The solution is filtered. The resulting solid is driedunder vacuum to give the title compound (6.0 g, 38 mmol).

[0754]¹H NMR (CDCl₃, 300 MHz) δ8.03 (s, 1H), 7.89 (s, 1H), 7.57 (m, 2H),2.41 (s, 3H). EI MS, [M+H]⁺=507.

[0755] B. 4-Chloro-6-methyl-quinazoline

[0756] 6-Methyl-3H-quinazolin-4-one (1.1 g, 6.9 mmol) is dissolved intoluene (70 mL). To the solution is added triethyl amine (1.82 g, 18mmol) and P(O)Cl₃ (1.06 g, 6.9 mmol). The solution is heated to reflux.After 3 h, the solution is poured into water (100 mL). The solution isdiluted with EtOAc (200 mL). The layers are separated. The organic layeris washed with water, saturated NaHCO₃ (aq.) and saturated NaCl (aq.).The organic layer is dried over MgSO₄, filtered and concentrated. Thetitle compound is obtained as an oil (0.75 g, 4.2 mmol).

[0757]¹H NMR (CDCl₃, 300 MHz) δ8.98 (s, 1H), 8.04 (s, 1H), 7.98 (d, 1H),7.82 (d, 1H), 2.62 (s, 3H).

[0758] C. 6-Bromomethyl-4-chloro-quinazoline

[0759] The title compound is prepared as described in EXAMPLE 1, Part Fsubstituting 4-chloro-6-methyl-quinazoline for1-chloro-7-methylisoquinoline. The crude product is purified by columnchromatography eluting with a gradient of 5% EtOAc/hexanes to 10%EtOAc/hexanes to give the title compound as a white solid.

[0760]¹H NMR (CDCl₃, 300 MHz) δ9.08 (s, 1H), 8.23 (s, 1H), 8.00 (dd,2H), 4.68 (s, 2H).

[0761] D. 7-Methoxynaphthalene-2-sulfonic acid(2-oxopyrrolidin-3-(S)-yl)-amide

[0762] To a solution of trifluoroacetic acid/CH₂Cl₂ (20 mL) at 0° C. isadded (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (04 g, 2mmol), prepared as described in EXAMPLE 1, Part G. The resultingsolution is allowed to warm to ambient temperatures and is stirred for12 hours. The solution is then concentrated. The resulting oil isreconcentrated from toluene. The oil is then dissolved in CH₃CN (6 mL).To the solution is added CH₂Cl₂ (6 mL). The resulting solution is cooledto 0° C. and triethyl amine (0.67 g, 6.6 mmol) followed by7-methoxynaphthalene sulfonyl chloride (0.64 g, 2.5 mmol), prepared asdescribed in EXAMPLE 1, Part J, are added. The solution is stirred for 6hours. After this time, the solution is concentrated. The resultingcrude solid is triturated with EtOAc. The crude solid is then furtherpurified by column chromatography eluting with a gradient of 2.5%MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give the title compound (0.40 g, 1.25mmol) as a white foam.

[0763]¹H NMR (CDCl₃, 300 MHz) δ8.35 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H),7.28 (m, 2H), 5.65 (bs, 1H), 5.34 (bs, 1H), 3.94 (s, 3H), 3.67 (m, 1H),3.32 (m, 2H), 2.62 (m, 1H), 2.21 (m, 1H).

[0764] E. 7-Methoxynaphthalene-2-sulfonic acidmethyl-(2-oxopyrrolidin-3-(S)-yl)-amide

[0765] The title compound is prepared as described in EXAMPLE 6, Part Asubstituting 7-methoxynaphthalene-2-sulfonic acid(2-oxopyrrolidin-3-(S)-yl)-amide for 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.The crude product is purified by column chromatography eluting with agradient of 40% EtOAc/CH₂Cl₂ to 60% EtOAc/CH₂Cl₂ to give the titlecompound as a white solid.

[0766]¹H NMR (CDCl₃, 300 MHz) δ8.39 (s, 1H), 7.90 (d, 1H), 7.76 (m, 2H),7.28 (m, 2H), 6.42 (bs, 1H), 4.82 (m, 1H), 3.92 (s, 3H), 3.32 (m, 2H),2.80 (s, 3H), 2.31 (m, 1H), 2.05 (m, 1H).

[0767] F. 7 Methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide

[0768] To a solution of 7-methoxynaphthalene-2-sulfonic acidmethyl-(2-oxopyrrolidin-3-(S)-yl)amide (0.35 g, 1.04 mmol) in THF (7 mL)at 0° C. is added LiN(SiMe₃)₂ (1 mL, 1 mmol, 1 M solution in THF). Thesolution is stirred at 0° C. for 40 minutes. After this time,6-bromomethyl-4-chloro-quinazoline (0.24 g, 0.94 mmol) is added. Theresulting solution is stirred for 4 hours. The reacton is quenched bythe addition of a saturated NH₄Cl solution. The solution is diluted withEtOAc and water. The layers are separated. The organic layer is washedwith water and brine. The organic layer is dried over MgSO₄, filteredand concentrated. The crude product is purified by column chromatographyeluting with a gradient of 20% EtOAc/CH₂Cl₂ to 40% EtAc/CH₂Cl₂ to givethe title compound (0.25 g, 0.49 mmol) as a white solid.

[0769]¹H NMR (CDCl₃, 300 MHz) δ9.03 (s, 1H), 8.40 (s, 1H), 8.03 (m, 2H),7.89 (d, 1H), 7.81 (m, 3H), 7.28 (m, 2H) 5.00 (m, 1H), 4.75 (AB, 1H),4.50 (AB, 1H), 3.92 (s, 3H), 3.22 (m, 2H), 2.87 (s, 3H), 2.38 (m, 1H),2.03(m, 1H). FAB MS, [M+H]⁺=511.

[0770] G. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-quinazolin-6-yl-methyl)-2-oxopyrrolidin-3S)-yl]-methylamidetrifluoroacetate

[0771] To 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6ylmethyl)2-oxopyrrolidin-3-(S)-yl]-methylamide (0.05 g, 0.1 mmol) suspended in EtOH (10 mL) is addedtriethylamine (0.02 g, 0.2 mmol) and ammonium acetate (0.08 g, 1 mmol).The reaction is heated to 80° C. The solution is concentrated. Theresidue is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 80% CH₃CN/H₂O (0. 1% TFA) and the appropriate productfractions are lyophilized to provide the title compound (0.03 g, 0.05mmol) as a white solid.

[0772]¹H NMR (DMSO-d₆, 300 MHz) δ9.78 (bs, 2H), 8.78 (s, 1H), 8.36 (s,1H), 8.11 (s, 1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.68 (m,2H), 7.56 (s, 1H), 7.49 (s, 1H), 7.32 (dd, 1H), 4.93 (m, 1H), 4.50 (AB,2H), 3.82 (s, 3H), 3.15 (m, 2H), 2.62 (s, 3H), 2.02 (m, 1H), 1.78 (m,1H). FAB MS, [M+H]⁺=492.

EXAMPLE 29

[0773] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0774] A. 2-Amino-5-methylthiophene-3-carboxylic acid methyl ester

[0775] To a solution of methyl cyanoacetate (19.8 g, 200 mmol) in DMF(25 mL) is added triethyl amine (10.9 g, 108 mmol). To the solution isadded sulfur (6.4 g, 200 mmol). The solution is heated to 60° C. Over a20 minutes period, propionaldehyde (11.6 g, 200 mmol) is added dropwise.After addition, the solution is allowed to cool to ambient temperaturesover 1 hour. The solution is stirred for 16 hours. The reaction ispoured into water (300 mL). The resulting solution is extracted withEt₂O ( 2×200 mL). The combined Et₂O extracts are washed with water andsaturated NaCl (aq.). The organic layer is dried over MgSO₄, filteredand concentrated. The resulting crude product is recrystallized fromMeOH/CH₂Cl₂ to give the title compound (13.7 g, 80 mmol) as a yellowsolid.

[0776]¹H NMR (CDCl₃, 300 MHz) δ6.58 (s, 1H), 5.78 (bs, 2H), 3.78 (s,3H), 2.28 (s, 3H).

[0777] B. 2-Amino-5-methylthiophene-3-carboxylic acid

[0778] To a solution of 2-amino-5-methylthiophene-3-carboxylic acidmethyl ester (13.7 g, 80 mmol) in MeOH/H₂O/THF (400 mL, 1:1:1) is addedLiOH.H₂O (16 g, 400 mmol). The solution is heated to 50° C. After 4hours, the solution is concentrated. The resulting residue is dissolvedin water. The pH of the solution is adjusted to between 5-6 using 1 NHCl. The precipitate is collected by filtration, washed with a smallamount of water and is dried under vacuum. The title compound (12 g, 76mmol) is obtained as a yelow solid.

[0779] EI MS, [M]⁺=157.

[0780] C. 6-Methyl-thieno[2,3-d]pyrimidin-4-ol

[0781] The title compound is prepared as described in EXAMPLE 28, Part Asubstituting 2-amino-5-methylthiophene-3-carboxylic acid for2-amino-5-methyl benzoic acid. The crude product is purified by columnchromatography eluting with a gradient of 2% MeOH/CH₂Cl₂ to 6%MeOH/CH₂Cl₂ to give the title compound as a solid.

[0782] EI MS, [M]⁺=165.

[0783] D. 4-Chloro-6-methyl -thieno[2,3-d]pyrimidine

[0784] The title compound is prepared as described in EXAMPLE 28, Part Bsubstituting 6-methyl-thieno[2,3-d]pyrimidin-4-ol for6-methyl-3H-quinazolin-4-one. The crude product is purified by columnchromatography eluting with a gradient of CH₂Cl₂ to 5% EtOAc/CH₂Cl₂ togive the title compound as a solid.

[0785]¹H NMR (CDCl₃, 300 MHz) δ8.84 (s, 1H), 7.42 (s, 1H), 2.68 (s, 3H).

[0786] E. 6-Bromomethyl-4-chloro-thieno[2,3-d]pyrimidine

[0787] The title compound is prepared as described in EXAMPLE 1, Part Fsubstituting 4-chloro-6-methyl-thieno[2,3-d]pyrimidine for1-chloro-7-methylisoquinoline. The crude product is purified by columnchromatography eluting with a gradient of 70% CH₂Cl₂/hexanes to 100%CH₂Cl₂to give the title compound as a white solid.

[0788]¹H NMR (CDCl₃, 300 MHz) δ8.84 (s, 1H), 7.42 (s, 1H), 4.72 (s, 2H).

[0789] F.[1-(4-Chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0790] The title compound is prepared as described in EXAMPLE 1, Part Hsubstituting 6-bromomethyl-4-chloro-thieno[2,3-d]pyrimidine for7-bromomethyl-1-chloroisoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 20% EtOAc/CH₂Cl₂ to 30%EtOAc/CH₂Cl₂ to give the title compound as a white foam.

[0791]¹H NMR (CDCl₃, 300 MHz) δ8.80 (s, 1H), 7.31 (s, 1H), 5.15 (bs,1H), 4.75 (AB, 2H), 4.18 (m, 1H), 3.36 (m, 2H), 2.62 (m, 1H), 1.96 (m,1H), 1.42 (s, 9H).

[0792] G. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide_ps The title compound is prepared as described in EXAMPLE 1, Part Isubstituting[1-(4-chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester for[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester. The resulting product is then taken directly onas described in EXAMPLE 1, Part K. The crude product is purified bycolumn chromatography eluting with a gradient of 30% EtOAc/CH₂Cl₂ to 40%EtOAc/CH₂Cl₂ to give the title compound as a white solid.

[0793]¹H NMR (CDCl₃, 300 MHz) δ8.80 (s, 1H), 8.32 (s, 1H), 7.92 (d, 1H),7.76 (m, 2H), 7.24 (m, 3H), 5.51 (bs, 1H), 4.68 (s, 2H), 3.93 (s, 3H),3.78 (m, 1H), 3.32 (m, 2H), 2.62 (m, 1H), 2.12 (m, 1H).

[0794] H. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0795] The title compound is prepared as dscribed in EXAMPLE 28, Part Gsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide. The residue is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0796]¹H NMR (DMSO-d₆, 300 MHz) δ8.33 (m, 2H), 8.21 (d, 1H), 8.02 (m,2H), 7.91 (d, 1H), 7.70 (dd, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.30 (dd,1H), 4.58 (AB, 2H), 4.05 (m, 2H), 3.93 (s, 3H), 3.17 (m, 2H), 1.98 (m,1H), 1.55 (m, 1H). FAB MS, [M+H]⁺=484.

EXAMPLE 30

[0797]7-Methoxynaphthalene-2-sulfonicacid[2-(6-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0798] A. 4-Chloro-7-methyl-thieno[3,2-d]pyrimidine

[0799] The title compound is prepared as described in EXAMPLE 28, Part Bsubstituting 7-methyl-thieno[2,3-d]pyrimidin4-ol for6-methyl-3H-quinazolin-4-one. The crude product is purified by columnchromatography eluting with a gradient of CH₂Cl₂ to 10% EtOAc/CH₂Cl₂ togive the title compound as a solid.

[0800]¹H NMR (CDCl₃, 300 MHz) δ9.02 (s, 1H), 7.68 (s, 1H), 2.51 (s, 3H).

[0801] B. 7-Bromomethyl1chloro-thieno[3,2-d]pyrimidine

[0802] The title compound is prepared as described in EXAMPLE 1, Part Fsubstituting 4-chloro-7-methyl-thieno[3,2-d]pyrimidine for1-chloro-7-methylisoquinoline. The crude product is purified by columnchromatography eluting with a gradient of 5% EtOAc/hexanes to 10%EtOAc/hexanes to give the title compound as a white solid.

[0803]¹H NMR (CDCl₃, 300 MHz) δ9.04 (s, 1H), 8.08 (s, 1H), 4.77 (s, 2H).

[0804] C.[1-(4-Chloro1thieno[3,2-d]pyrimidin-7-ylmethyl1)2-oxopyrrolidin-3-(S)-yl-carbamic acid tert-butyl ester

[0805] The title compound is prepared as described in EXAMPLE 1, Part Hsubstituting 7-bromomethyl4-chloro-thieno[3,2-d]pyrimidine for7-bromomethyl-1-chloroisoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 20% EtOAc/CH₂Cl₂ to 30%EtOAc/CH₂Cl₂ to give the title compound as a white foam.

[0806]¹H NMR (CDCl₃, 300 MHz) δ8.95 (s, 1H), 8.06 (s, 1H), 5.18 (bs,1H), 4.76 (AB, 2H), 4.13 (m, 1H), 3.44 (m, 1H), 3.37 (m, 1H), 2.64 (m,1H), 1.92 (m, 1H), 1.42 (s, 9H).

[0807] D. 7-Methoxylnaphthalene-2-sulfonicacid[1-(4-chloro-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide

[0808] The title compound is prepared as described in EXAMPLE 1, Part Isubstituting[1-(4-chloro-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester for[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester. The resulting product is then taken directly onas described in EXAMPLE 1, Part K. The crude product is purified bycolumn chromatography eluting with a gradient of 30% EtOAc/CH₂Cl₂ to 40%EtOAc/CH₂Cl₂ to give the title compound as a white solid.

[0809]¹H NMR (CDCl₃, 300 MHz) δ8.92 (s, 1H), 8.32 (s, 1H),7.96 (s, 1H),7.86 (d, 1H), 7.74 (m, 2H), 7.28 (d, 1H), 7.19 (d, 1H), 5.64 (bs, 1H),4.71 (AB, 2H), 3.93 (s, 3H), 3.72 (m, 1H), 3.44 (m, 1H), 3.32 (m, 1H),2.52 (m, 1H), 2.05 (m, 1H).

[0810] E. 7-Methoxynaphthalene-2-sulfonicacid[2-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0811] The title compound is prepared as described in EXAMPLE 28, Part Gsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide. The residue is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0812]¹H NMR (DMSO-d₆, 300 MHz) δ8.55 (s, 1H), 8.35 (bs, 3H), 8.14 (d,1H), 8.00 (m, 2H), 7.93 (d, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.32 (dd,1H), 4.49 (AB, 2H), 4.09 (m, 1H), 3.90 (s, 3H), 3.18 (m,.2H), 1.96 (m,1H), 1.54 (m, 1H). FAB MS, [M+H]⁺=483. Elemental analysis calculatedwith 1.5 mol H₂O and 1.5 mol trifluoroacetate cal. C=44.75%, H=3.83%,N=10.44%, found C=44.75%, H=3.77%, N=11.12%.

EXAMPLE 31

[0813] 7-Methoxynaphthalene-2-sulfonicacid[1-(7-amino-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0814] A. 3-Bromomethyl-7-chlorothieno[2,3-c]pyridine

[0815] The title compound is prepared as described in EXAMPLE 1, Part Fsubstituting 7-chloro-3-methyl-thieno[2,3-c]pyrimidine for1-chloro-7-methylisoquinoline. The crude product is purified by columnchromatography eluting with a gradient of 5% EtOAc/hexanes to 10%EtOAc/hexanes to give the title compound as a white solid.

[0816]¹H NMR (CDCl₃, 300 MHz) δ8.38 (d, 1H), 7.73 (s, 1H), 7.71 (d, 1H),4.72 (s, 2H).

[0817] B.[1-(7-Chloro-thieno[2,3-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0818] The title compound is prepared as described in EXAMPLE 1, Part Hsubstituting 3-bromomethyl-7-chloro-thieno[2,3-c]pyridine for7-bromomethyl1-chloroisoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 20% EtOAc/CH₂Cl₂ to 40%EtOAc/CH₂Cl₂ to give the title compound as a white foam.

[0819]¹H NMR (CDCl₃, 300 MHz) δ8.28 (d, 1H), 7.74 (d, 1H), 7.64 (s, 1H),5.18 (bs, 1H), 4.68 (AB, 2H), 4.17 (m, 1H), 3.18 (m, 2H), 2.54 (m, 1H),1.86 (m, 1H), 1.42 (s, 9H).

[0820] C. 7-Methoxynaphthalene-2-sulfonicacid[1-(7-chloro-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide

[0821] The title compound is prepared as described in EXAMPLE 1, Part Isubstituting[1-(7-chloro-thieno[2,3-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester for[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester. The resulting product is then taken directly onas described in EXAMPLE 1, Part K. The crude product is purified bycolumn chromatography eluting with a gradient of 30% EtOAc/CH₂Cl₂ to 40%EtOAc/CH₂Cl₂ to give the title compound as a white solid.

[0822]¹H NMR (DMSO-d₆, 300 MHz) δ833 (s, 1H), 8.30 (d, 1H), 8.16 (d,1H), 8.07 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H), 7.78 (d, 1H), 7.67 (d,1H), 7.51 (d, 1H), 7.28 (dd, 1H), 4.58 (AB, 2H), 4.08 (m, 1H), 3.88 (s,2H), 1.89 (m, 1H), 1.48 (m, 1H).

[0823] D. 7-Methoxynaphthalene-2-sulfonic acid[1-(7-amino-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0824] The title compound is prepared as described in EXAMPLE 28, Part Gsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(7-chloro-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide. The residue is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0825]¹H NMR (DMSO-d₆, 300 MHz) δ8.90 (bs, 3H), 8.34 (s, 1H), 8.16 (d,1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.34 (m,3H), 7.23 (dd, 1H), 4.64 (AB, 2H), 4.08 (m, 1H), 3.88 (s, 3H), 3.09 (M,2H), 2.11 (m, 1H), 1.60 (m, 1H). FAB MS, [M+H]⁺=483.

EXAMPLE 32

[0826] 7-Methoxynaphthalene-2-sulfonicacid[1-(7-hydroxy-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0827] A. 7-Methoxynaphthalene-2-sulfonicacid[1-(7-hydroxy-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0828] The title compound is prepared as described in EXAMPLE 28, Part Gsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(7-chloro-thieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-quinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide. The residue is purified by RP-HPLC eluting in a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0829]¹HNMR (DMSO-d₆, 300 MHz) δ8.36 (s, 1H), 8.18 (d, 1H), 8.01 (d,1H), 7.92 (d, 1H), 7.86 (s, 1H), 7.68 (d, 1H), 7.52 (s, 1H), 7.28 (m,3H), 6.62 (d, 1H), 4.42 (AB, 2H), 4.00 (m, 1H), 3.88 (s, 3H), 3.04 (m,2H), 1.89 (m, 1H), 1.44 (m, 1H). FAB MS, [M+H]⁺=484.

EXAMPLE 33

[0830] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0831] A. 3-(5-Methyl-thiophen-2-yl)-acrylic acid methyl ester

[0832] To 5-methyl-thiophene-2-carboxaldehyde (5 g, 40 mmol) in CH₂Cl₂(100 mL) is added methyl (triphenylphosphoranylidene) acetate (13.3 g,40 mmol). The solution is stirred for 72 hours. After this time, thesolution is concentrated. The residue is slurried in Et₂O. The solutionis filtered through a bed of Celite. The collected liquid isconcentrated. The residue is purified by column chromatography elutingwith a gradient of 50% EtOAc/hexanes to 60% EtOAc/hexanes to give thetitle compound (4.5 g,. 25 mmol) as an oil.

[0833]¹H NMR (CDCl₃, 300 MHz) δ7.69 (d, 1H), 7.04 (d, 1H), 6.71 (d, 1H),6.11 (d, 1H), 3.79 (s, 3H), 2.49 (S, 3H).

[0834] B. 3-(5-Methyl-thiophen-2-yl)-acrylic acid

[0835] The title compound is prepared as described in EXAMPLE 29, Part Bsubstituting 3-(5-methyl-thiophen-2-yl)-acrylic acid methyl ester for2-amino-5-methylthiophene-3-carboxylic acid methyl ester. The titlecompound is obtained by filtration as a white solid.

[0836]¹H NMR (CDCl₃, 300 MHz) δ7.58 (d, 1H), 7.24 (d, 1H), 7.82 (d, 1H),5.98 (d, 1H), 2.46 (s, 3H).

[0837] C. 2-Methyl-5H-thieno[3,2-c]pyridin-4-one

[0838] The title compound is prepared as described in EXAMPLE 1, Part A,substituting 3-(5-methyl-thiophen-2-yl)-acrylic acid for3-p-tolyl-acrylic acid. The product is then treated as described inEXAMPLE 1, Part B, C, and D. The crude product is purified by columnchromatography eluting with 1% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give thetitle compound as a white solid.

[0839]¹H NMR (CDCl₃, 300 MHz) δ11.72 (bs, 1H), 7.31 (s, 1H), 7.18 (d,1H), 6.68 (d, 1H), 2.58 (s, 3H). EI MS, [M]⁺=165.

[0840] D. 4-Chloro-2-methyl-thieno[3,2-c]pyridine

[0841] The title compound is prepared as described in EXAMPLE 1, Part E,substituting 2-methyl-5H-thieno[3,2-c]pyridin-4-one for7-methyl-2H-isoquinolin-1-one. The crude product is purified by columnchromatography eluting with a gradient of 70% CH₂Cl₂/hexanes to 100%CH₂Cl₂to give the title compound as a white solid.

[0842]¹H NMR (CDCl₃, 300 MHz) δ8.13 (d, 1H), 7.58 (d, 1H), 7.16 (d, 1H),2.61 (s, 3H).

[0843] E. 2-Bromomethyl-4-chloro-thieno[3,2-c]pyridine

[0844] The title compound is prepared as described in EXAMPLE 1, Part Fsubstituting 4-chloro-2-methyl-thieno[3,2-c]pyridine for1-chloro-7-methylisoquinoline. The crude product is purified by columnchromatography eluting with a gradient of 5% EtOAc/hexanes to 10%EtOAc/hexanes to give the title compound as a white solid.

[0845]¹H NMR (CDCl₃, 300 MHz) δ8.21 (d, 1H), 7.63 (d, 1H), 7.49 (s, 1H),4.80 (s, 2H).

[0846] F.I-(4-Chloro-thieno[3,2-c]pyridin-2-ylmethyl2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester

[0847] The title compound is prepared as described in EXAMPLE 1, Part Hsubstituting 2-bromomethyl-4-chloro-thieno[3,2-c]pyridine for7-bromomethyl1-chloroisoquinoline. The crude product is purified bycolumn chromatography eluting with a gradient of 20% EtOAc/CH₂Cl₂ to 30%EtOAc/CH₂Cl₂ to give the title compound as a white foam.

[0848]¹H NMR (CDCl₃, 300 MHz) δ8.22 (d, 1H), 7.63 (d, If), 7.39 (s, 1H),5.13 (bs, 1H), 4.78 (AB, 2H), 4.21 (m, 1H), 3.33 (m, 2H), 2.62 (M, 1H),1.90 (m, 1H), 1.42 (s, 9H).

[0849] G.3-(S)-Amino-1(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride

[0850] The title compound is prepared as described in EXAMPLE 1, Part Isubstituting1-(4chloro-thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester for[1-(1-chloro-isoquinolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester. The title compound is obtained as a white solid.

[0851]¹H NMR (DMSO-d₆, 300 MHz) δ8.50 (bs, 3H), 8.22 (d, 1H), 8.06 (d,1H), 7.51 (s, 1H), 4.81 (AB, 2H), 4.04 (m, 2H), 3.32 (m, 2H), 2.31 (m,1H), 1.96 (m, 1H).

[0852] H. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide

[0853] The title compound is prepared as described in EXAMPLE 1, Part Ksubstituting3-amino-1-(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-onefor 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride. The title compound is obtained as a white solid.

[0854]¹H NMR (DMSO-d₆, 300 MHz) δ8.36 (s, 1H), 8.28 (d, 1H), 8.18 (d,1H), 8.02 (m, 2H), 7.91 (d, 1H), 7.69 (d, 1H), 7.56 (d, 1H), 7.42 (s,1H), 7.29 (dd, 1H),4.66 (AB,2H),4.10 (m, 1H), 3.88 (s, 3H),3.14 (m,2H),1.97 (m, 1H), 1.58 (m, 1H).

[0855] I. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-amino-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0856] The title compound is prepared as described in EXAMPLE 1, Part Lsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.The resulting product is then treated as described in EXAMPLE 1, Part M.The residue is purified by RP-HPLC eluting with a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0857]¹H NMR (DMSO-d₆, 300 MHz) δ8.58 (bs, 3H), 8.32 (s, 1H), 8.26 (d,1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.78 (s, 1H), 7.69 (m, 2H), 7.49 (dd,1H), 7.28 (dd, 1H), 4.62 (AB, 2H), 4.02 (m, 1H)H), 3.88 (s, 3H), 3.13(m, 2H), 1.96 (m, 1H), 1.58 (m, 1H). FAB MS, [M+H]⁺=483.

EXAMPLE 34

[0858] 7-Methoxynaphthalene-2-sulfonicacid[1-(4-hydroxy-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0859] A. 7-Methoxynaphthalene-2-sulfonicacid[1-(4-hydroxy-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0860] The title compound is prepared as described in EXAMPLE 1, Part Lsubstituting 7-methoxynaphthalene-2-sulfonicacid[1-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidefor 7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.The resulting product is then treated as described in EXAMPLE 1, Part M.The residue is purified by RP-HPLC eluting with a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0861]¹H NMR (DMSO-d₆, 300 MHz) δ11.32 (bs, 1H), 8.33 (s, 1H), 8.20 (d,1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.69 (d, 1H), 7.52 (d, 1H), 7.46 (s,1H), 7.30 (m, 2H), 7.19 (m, 1H), 6.71 (d, 1H), 4.52 (AB, 2H), 4.06 (m,1H), 3.88 (s, 3H), 3.10 (m, 2H), 1.90 (m, 1H), 1.50 (m, 1H). FAB MS,[M+H]⁺=484.

EXAMPLE 35

[0862] Benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate.

[0863] A. Benzo[b]thiophene-2-sulfonicacid[1-(4-chloro-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide

[0864] The title compound is prepared as described in EXAMPLE 1, Part Ksubstituting3-amino-1-(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-onefor 3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride and benzo[b]thiophene-2-sulfonyl chloride for7-methoxynaphthalene-2-sulfonyl chloride. The title compound is obtainedas a white solid.

[0865]¹H NMR (CDCl₃, 300 MHz) δ8.21 (d, 1H), 7.96 (s, 1H), 7.90 (m, 2H),7.64 (d, 1H), 7.49 (m, 2H), 7.39 (s, 1H), 5.58 (bs, 1H), 4.76 (s, 2H),3.97 (m, 1H), 3.38 (m, 2H), 2.68 (m, 1H), 2.18 (m, 1H).

[0866] C. Benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[0867] The title compound is prepared as described in EXAMPLE 1, Part Lsubstituting benzo[b]thiophene-2-sulfonic acid[1-(4-chloro-thieno[3,2-cpyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for7-methoxynaphthalene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide.The resulting product is then treated as described in EXAMPLE 1, Part M.The residue is purified by RP-HPLC eluting with a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[0868]¹H NMR (DMSO-d₆, 300 MHz) δ8.70 (d, 1H), 8.55 (bs, 2H), 8.07 (m,3H), 7.78 (s, 1H), 7.70 (d, 1H), 7.49 (m, 3H), 4.66 (AB, 2H), 4.16 (m,1H), 3.24 (m, 2H), 2.12 (m, 1H), 1.72 (m, 1H). FAB MS, [M+H]⁺=459.

EXAMPLE 36

[0869] 5-Pyridin-4-Yl-thiophene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0870] A. 4-Thiophen-2-yl-pyridine

[0871] 2-Bromothiophene (7.6 mL, 78.5 mmol) is added dropwise to a flameand vacuum dried three-necked round-bottomed flask fitted with acondenser, stopper and magnesium (2 g, 82.3 mmol) in diethyl ether (70mL). The resulting grey solution is stirred at reflux for 1.5 hours.Meanwhile 4-bromopyridine hydrochloride is converted to the free base inthe following manner: 4-Bromopyridine hydrochloride (15.3 g, 78.7 mmol)is dissolved in water (100 mL), and cooled in an ice bath. Oneequivalent of 1 N NaOH (ca. 100 mL) is added dropwise until pH is ˜5.6.The ice-cooled aqueous solution is extracted with hexane (3×150 mL) andthe combined organic layers are dried over MgSO₄ and filtered. Hexane isremoved under vacuum (11 mm Hg) while cooling in an ice-bath to a volumeof ca. 30 mL. The resulting colorless clear solution is diluted with THF(150 mL) under N₂. The Grignard reagent is then cooled to roomtemperature and added via cannula to the solution of NiCl₂dppp (0.54 g,1 mmol) and 4-bromopyridine in THF. The resulting dark solution isrefluxed overnight. The reaction mixture is then poured over saturatedNH₄Cl solution and extracted with diethyl ether (3×200 mL). The combinedethereal layers are acidified with 2 N HCl (300 mL) and the aqueouslayer is washed with diethyl ether. The aqueous layer is then cooled inan ice-bath and neutralized with sodium bicarbonate. The aqueous layeris extracted with ethyl acetate (3×200 mL) and the combined organiclayers are dried over MgSO₄, filtered and concentrated to give a brownsolid. The crude solid is taken up in hot hexanes and the yellowsolution is separated from the insoluble black solid. The hexanesolution is concentrated and the above procedure is repeated. Uponcooling the hexane solution, yellow solid precipitates form. The yellowsolid is collected to give the title compound (8.99 g, 55.8 mmol).

[0872]¹H NMR (CDCl₃, 300 MHz) δ8.60 (d, 2H), 7.51 (m, 1H), 7.49 (d, 2H),7.42 (dd, 1H), 7.14 (dd, 1H). EI MS, [M.]⁺=161.

[0873] B. 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride

[0874] To a solution of 4-thiophen-2-yl-pyridine (3.33 g, 20.7 mmol) inTHF (137 mL) at −78° C. is added n-BuLi (8.7 mL of a 2.5 M solution inhexanes, 21.7 mmol). After stirring for 15 minutes, SO₂ gas is bubbledthrough the solution for 30 minutes. The solution is then allowed towarm to room temperature and stirred overnight. The solution isconcentrated to dryness and the resulting solid is suspended in hexane(100 mL). To the ice-cooled solution is added sulfuryl chloride (1.7 mL.21.7 mmol). The ice bath is removed and the suspension is stirred for 2hours. The mixture is then concentrated to dryness and diluted withethyl acetate and washed with saturated NaHCO₃ (aq), water and brine.The organic layer is dried over MgSO₄, filtered and concentrated to givea yellow solid as the title product (3.39 g, 13.1 mmol) which is used inthe subsequent step without further purification.

[0875]¹H NMR (CDCl₃, 300 MHz) δ8.75(d, 2H), 8.60 (d, 1H), 7.90 (d, 1H),7.51 (d, 2H), EI, [M]⁺=259, 261, Cl pattern.

[0876] C. 5-Pyridin-4-yl-thiophene-2-sulfonicacid-[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0877] 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride is added to asolution of3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (0.12 g, 0.38 mmol) in pyridine (2 mL). The resultingmixture is stirred overnight then concentrated to dryness. The residueis diluted with methylene chloride and washed with saturated NaHCO₃solution and brine. The organic layer is dried over MgSO₄, filtered andconcentrated to give 105 mg of a crude solid. The crude product ispurified by column chromatography eluting with 5% MeOH/CH₂Cl₂ to affordthe title product (0.026 g, 0.052 mmol) as a white solid.

[0878]¹H NMR (CDCl₃, 300 MHz) δ8.67 (d, 2H), 8.30 (d, 1H), 8.14 (s, 1H),7.83 (d, 1H), 7.70 (d, 1H), 7.57-7.61 (m, 2H), 7.48-7.46 (m, 3H), 5.60(bs, 1H), 4.67 (AB, 2H), 3.98 (m, 1H), 3.29 (m, 2H), 2.68 (m, 1H), 2.15(m, 1H). APCI MS, [M+H]⁺=499, 501, Cl pattern.

[0879] D. 5-Pyridin-4-yl-thiophene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0880] Ammonium acetate (0.12 g, 1.56 mmol), phenol (0.049 g, 0.52mmol), and 5-pyridin-4-yl-thiophene-2-sulfonicacid-[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.026 g, 0.052 mmol) is heated to 90° C. for 6 hours then cooled toroom temperature. The product is purified by RP-HPLC eluting with agradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and theappropriate product fractions are lyophilized to give the title compound(0.005 g, 0.007 mmol) as a white solid.

[0881]¹H NMR (DMSO-d₆, 300 MHz) δ13.0 (bs, 1H), 9.0 (bs, 1H), 8.60-8.70(m, 3H), 8.29 (s, 1H), 7.91 (d, 1H), 7.89 (d, 1H), 7.71-7.80 (m, 4H),7.66 (d, 1H), 7.23 (d, 1H). FAB MS, [M+H]⁺=480.

EXAMPLE 37

[0882] 5-Pyridin-3-yl-thiophene-2-sulfonicacid-[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0883] A. 3-Thiophen-2-yl-pyridine

[0884] The title compound is prepared as described in EXAMPLE 36, Part Ausing 3-bromopyridine in place of 4-bromopyridine hydrochloride.

[0885]¹H NMR (CDCl₃, 300 MHz) δ8.89 (dd, 1H), 8.52 (dd, 1H), 7.87 (ddd,1H), 7.38 (s, 1H), 7.36 (d, 1H), 7.31 ((m, 1H), 7.12 (dd, 1H). EI,[M]⁺=161.

[0886] B. 5-Pyridin-3-yl-thiophene-2-sulfonyl chloride

[0887] The title compound is prepared as described in EXAMPLE 36, Part Busing 3-thiophen-2-yl-pyridine in place of 4-thiophen-2-yl-pyridine.

[0888]¹H NMR (CDCl₃, 300 MHz) δ8.95 (bs, 1H), 8.70 (bs, 1H), 7.95 (d,1H), 7.90 (d, 1H), 7.45 (bs, 1H), 7.44 (d, 1H). EI, [M]⁺=259, 261, Clpattern.

[0889] C. 5-Pyridin-3-yl-thiophene-2-sulfonicacid-[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0890] Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a solutionof 5-pyridin-3-yl-thiophene-2-sulfonyl chloride (0.22 g, 0.85 mmol) and3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (0.22 g, 0.71 mmol) in CH₃CN (5 mL). The suspension isstirred at room temperature overnight then concentrated to dryness. Theresidue is diluted with methylene chloride and washed with saturatedNaHCO₃ solution and brine. The organic layer is dried over MgSO₄,filtered, concentrated, and then purified by column chromatographyeluting with a gradient of 1% MeOH/CH₂Cl₂ to 5% MeOH/CH₂Cl₂ to give theproduct (0.23 g, 0.45 mmol) as a white solid.

[0891]¹H NMR (CDCl₃, 300 MHz) δ8.89 (d, 1H), 8.63 (dd, 1H), 8.30 (d,1H), 8.13 (d, 1H), 7.82-7.89 (m, 2H), 7.70 (d, 1H), 7.57-7.68 (m, 2H),7.33-7.40 (m, 2H), 5.45 (d, 1H), 4.67 (AB, 2H), 3.95 (m 1H), 3.28 (m,2H), 2.75 (m, 1H), 2.10 (m, 1H). Ion spray MS, [M+H]⁺=499, 501, Clpattern.

[0892] D. 5-Pyridin-3-yl-thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0893] The title compound is prepared as described in EXAMPLE 36, Part Dusing 5-pyridin-3-yl-thiophene-2-sulfonicacid-[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidein place of 5-pyridin-4-yl-thiophene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideand heating at 100° C. overnight. The crude product is purified byRP-HPLC eluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100%CH₃CN. The appropriate product fractions are lyophilized to give thetitle compound as a white solid.

[0894]¹H NMR (DMSO-d₆, 300 MHz) δ12.95 (bs, 1H), 8.90-9.05 (m, 2H),8.55-8.65 (m, 2H), 8.31 (s, 1H), 8.17 (m, 1H), 8.96 (d, 1H), 8.82 (d,1H), 7.70-7.72 (m, 2H), 7.65 (d, 1H), 7.53 (dd, 1H), 7.21 (d, 1H), 4.60(AB, 2H), 4.30 (m, 1H), 3.25 (m, 2H), 2.29 (m, 1H), 1.78 (m, 1H). FABMS, [M+H]⁺=480.

EXAMPLE 38

[0895] Benzothiophene-2-sulfonicacid[1-(4-aminoquinolin-6-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0896] A. 4-Chloro-6-methylquinoline

[0897] 6-Methyl-(1H)-quinolin-4-one (1.57 g, 9.7 mmol) in 20 mLphosphorus oxychloride is heated to 110° C. for 4 hours. The mixture iscooled to room temperature then diluted with ice water (˜200 mL) and thepH is adjusted to ca. 10 by the slow addition of 10 N NaOH. The aqueoussolution is extracted with methylene chloride (4×250 mL) and thecombined organic layers washed with brine, dried over Na₂SO₄, filteredand concentrated. The crude residue is filtered through silica gel with33% EtOAc/hexanes to give the product (1.05 g, 5.9 mmol) as a yellowsolid.

[0898]¹H NMR (CDCl₃, 300 MHz) δ8.69 (d, 1H), 8.0 (m, 2H), 7.58 (dd, 1H),7.44 (d, 1H), 2.58 (s, 3H1). EI MS, [M.]⁺=177, 179, Cl pattern.

[0899] B. 6Bromomethyl-4-chloro-quinoline

[0900] N-Bromosuccinimide (1.1 g, 6.19 mmol) and 70% benzoyl peroxide(0.215 g, 0.62 mmol) are added to a solution of4-chloro-6-methylquinoline (1.05 g, 5.93 mmol) in 35 mL carbontetrachloride. The resulting mixture is heated to reflux overnight thencooled to room temperature and diluted with methylene chloride. Theorganic layer is washed with 1 N NaOH, dried over Na₂SO₄, filtered andconcentrated. The residue is purified by column chromatography elutingwith 33% EtOAc/hexanes to give the product (0.915 g, 3.57 mmol) as awhite solid.

[0901]¹H NMR (CDCl₃, 300 MHz) δ8.73 (d, 1H), 8.13 (d, 1H), 8.07 (d, 1H),7.74 (dd, 1H), 7.42 (d, 1H), 4.67 (s, 2H). Ion Spray, [M+H]⁺=256, 258,260 Cl, Br pattern.

[0902] C. 3-(S)-Amino-1-(4-Chloroquinolin-6-ylmethyl)-pyrrolidin-2-onehydrochloride

[0903] Sodium hydride (0.096 g, 2.4 mmol, 60% by weight) is added to asolution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester(0.4 g, 2 mmol) in 15 mL of THF at 0° C. The mixture is stirred for 30minutes then a solution of 6-bromomethyl-4chloroquinoline (0.513 g, 2mmol) in 15 mL THF is added slowly. The resulting solution is warmed toroom temperature over 4 hours. The reaction mixture is quenched withsaturated ammonium chloride solution then diluted with EtOAc. Theorganic layer is separated, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue is dissolved in ethyl acetate (50mL), and saturated with HCl gas at 0° C. The solution is stirred at 0°C. for 15 minutes, then the solution is warmed to room temperature.After four hours at room temperature, the solid that precipitates iscollected, and washed with ether to give the title compound (0.445 g,1.43 mmol) as a pale yellow solid.

[0904]¹H NMR (DMSO-d₆, 300 MHz) δ9.05 (d, 1H), 8.78 (bs, 3H), 8.27 (d,1H), 8.23 (s, 1H), 8.02 (d, 1H), 7.96 (d, 1H), 4.67 (AB, 2H), 4.12 (m,1H), 3.35 (m, 2H), 2.43 (m, 1H), 2.09 (m, 1H). Ion Spray MS, [M+H]⁺=276,278.

[0905] D. Benzothiophene-2-sulfonicacid[1-(4-chloroquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0906] 3-(S)-Amino-1-(4-chloroquinolin-6-ylmethyl)-pyrrolidin-2-onehydrochloride (0.12 g, 0.38 mmol) is suspended in 15 mL CH₃CN. To thissolution is added triethylarpine (110 mL, 0.79 mmol) followed bybenzothiophene-2-sulfonyl chloride (0.094 g, 0.40 mmol). The mixture isstirred overnight at room temperature, subjected to aqueous work up thenconcentrated to dryness. The crude product is purified by columnchromatography eluting with 2-10% MeOH/CH₂Cl₂ to give the title compound(0.11 g, 0.23 mmol) as an off-white solid.

[0907]¹H NMR (CDCl₃, 300 MHz) δ8.77 (d, 1H), 8.08 (d, 1H), 8.04 (s, 1H),7.97 (s, 1H), 7.88 (m, 2H), 7.58 (dd, 1H), 7.49 (m, 3H), 6.01 (bs, 1H),4.67 (AB, 2H), 4.03 (t, 11H), 3.27 (m, 2H), 2.65 (m, 1H), 2.16 (m, 1H).FAB MS, [M+H]⁺=472, 474, Cl pattern.

[0908] E. Benzothiophene-2-sulfonic acid1-(4-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0909] Benzothiophene-2-sulfonicacid[1-(4-chloroquinolin-6ylmethyl)-2-oxopyrrolidin-3-(Syl]-amide (0.11g, 0.23 mmol) is treated with phenol (1 g) and ammonium acetate (0.22 g,2.8 mmol) at 110° C. as previously described. After five hours themixture is cooled to room temperature and diluted with 100 mL methylenechloride. The organic solution is washed with 1 N NaOH (2×) and saline,dried over Na₂SO₄, filtered and concentrated. The residue is purified byHPLC eluting with a gradient of 10 to 100% CH₃CN/0.1% TFA in water over30 minutes. Fractions containing pure product are lyophilized to givethe title compound as a white solid (0.02 g, 0.044 mmol).

[0910]¹H NMR (CD₃OD, 300 MHz) δ8.25 (d, 1H), 8.13 (s, 1H), 7.97 (s, 1H),7.85 (m, 2H), 7.80 (AB, 2H), 7.48 (m, 2H), 6.80 (d, 1H), 4.64 (s, 2H),4.35 (t, 1H), 3.31 (m, 2H), 2.48 (m, 1H), 1.89 (m, 1H). Ion Spray MS,[M+H]⁺=453.

EXAMPLE 39

[0911] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0912] A. 1-Phenoxy-6-bromomethyl-isoquinoline

[0913] To 1-chloro-6-methyl-isoquinoline (2.28 g, 13.3 mmol), which isprepared as described in EXAMPLE 1, Part E, substituting6-methyl-2H-isoquinolin-1-one for 7-methyl-2H-isoquinolin-1-one, isadded 20 g of phenol. The solution is heated to 80° C. and KOH (3.73 g,66.4 mmol) is added. After the addition, the solution is stirred andheated to 140° C. After 24 hours, the solution is cooled to ambienttemperatures, and dissolved in CH₂Cl₂. The organic solution is washedwith H₂O. The organic layer is washed with 1 N NaOH and saturated NaCl.the organic layer is dried over MgSO₄, filtered and concentrated. Theresulting residue is dissolved in 50 mL of CCL₄. to the resultingsolution is added NBS (2.01 g, 11.27 mmol) and benzoyl peroxide (0.6 g,1.73 mmol). The solution is heated to reflux. After 16 hours, thesolution is diluted with CH₂Cl₂. The organic layer is washed with 10%Na₂CO₃ and saturated NaCl. The organic layer is dried over MgSO₄,filtered and concentrated. The residue is purified by columnchromatography eluting with 5% EtOAc/hexanes and 10% EtOAc/hexanes. MS,[M]⁺=313, 315, Br pattern.

[0914] B.[1-(1-Chloro-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-carbamicacid benzyl ester

[0915] To a solution of (2-oxopyrrolidin-3-(S)-yl) -carbamic acid benzylester (0.15 g, 0.64 mmol) in 6 mL of 10:1 THF:DMF at 0° C. is added a60% NaH dispersion (0.03 g, 0.71 mmol) followed by1-phenoxy-6-bromomethyl-isoquinoline (0.2 g, 0.64 mmol). After 16 hours,the solution is treated with 10 mL of saturated NH₄Cl. The solution isdiluted with CH₂Cl₂. The organic layer is washed with H₂O and saturatedNaCl. The resulting product is suspended in 5 g of NH₄OAc and heated to120° C. After 36 hours, the solution is cooled to ambient temperatures.The solution is diluted with H₂O and CH₂Cl₂. The organic layer is washedwith H₂O and saturated NaCl. The organic layer is dried over MgSO₄,filtered and concentrated. The residue is purified by columnchromatography eluting with 5% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂ to givethe product as a white solid (0.043 g, 0.11 mmol).

[0916]¹H NMR (CDCl₃, 300 MHz) δ8.41 (d, 1H), 7.98 (d, 1H), 7.63 (s, 1H),7.42 (m, 3H), 7.32 (m, 4H), 7.22 (m, 5H), 5.40 (bs, 1H), 5.14 (s, 2H),4.64 (AB, 2H), 4.30 (m, 1H), 3.24 (m, 2H), 2.66 (m, 1H), 1.92 (m, 1H).FAB MS, [M+H]⁺=391.

[0917] C. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[-1-(1-amino-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0918] To a solution of[1-(1-chloro-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-carbamicacid benzyl ester (0.043 g, 0.11 mmol) in 4 mL of MeOH, is added 10% byweight Pd/C (0.02 g). The atmosphere above the reaction is replaced byhydrogen. After 16 hours, the solution is filtered through Celite andthe Celite is washed with MeOH. The collected solution is concentrated.The resulting residue is dissolved in 3 mL of CH₂Cl₂:EtOH (2:1). To thesolution is added Et₃N (0.01 g, 0.11 mmol) and6-Chloro-benzo[b]thiophene sulfonyl chloride (0.03 g, 0.11 mmol). After4 hours, the solution is concentrated. The residue is purified byRP-HPLC eluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80%CH₃CN/H₂O (0.1% TFA). The appropriate fractions are lyophilized toprovide the title compound as a white solid.

[0919]¹H NMR (DMSO-d₆, 300 MHz) δ8.95 (bs, 3H), 8.71 (d, 1H), 8.46 (d,1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.71 (s, 1H), 7.63 (d, 1H), 7.52 (m,2H), 7.12 (d, 1H), 4.52 (AB, 2H), 4.28 (m, 1H), 3.17 (m, 2H), 2.12 (m,1H), 1.67(m, 1H). FAB MS, [M+H]⁺=487, 489, Cl pattern.

EXAMPLE 40

[0920] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0921] A.[1-(1-(1,2,3,4-Tetrahydro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]carbamicacid tert-butyl ester

[0922] To a solution of[1-(1-chloro-isoquinoline-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]carbamicacid tert-butyl ester (0.48 g, 1.28 mmol) in 50 mL of AcOH:MeOH (1:1) isadded 5% by weight PtO₂/C (0.1 g). The atmosphere over the reaction isreplaced by hydrogen. After 16 hours, the solution is filtered throughCelite and the Celite is washed with MeOH. The organic solution isconcentrated to give the product as a white foam.

[0923] MS, [M+H]⁺=346.

[0924] B.7-(3-tert-Butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid benzyl ester

[0925] To a solution of[1-(1-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]carbamicacid tert-butyl ester (0.54g, 1.58 mmol) in 50 mL of CH₂Cl₂ is addedtriethyl amine (0.66 mL, 4.73 mmol) and benzyl chloroformate (0.39 mL,1.89 mmol). The solution is stirred for 16 hours. After this time, thesolution is diluted with CH₂Cl₂. The organic solution is washed with H₂Oand saturated NaCl. The residue is purified by column chromatographyeluting with 20% EtOAc/CH₂Cl₂.

[0926]¹H NMR (CDCl₃, 300 MHz) δ7.35 (m, 5H), 7.08 (d, 1H), 7.02 (d, 1H),6.95 (s, 1H), 5.14 (s, 2H), 5.10 (m, 1H), 4.58 (s, 2H), 4.38 (m, 2H),4.16 (m, 1H), 3.68 (m, 2H), 3.18 (dd, 2H), 2.78 (m, 2H), 2.59 (m, 1H),1.81 (m, 1H), 1.42 (s, 9H).

[0927] FAB MS, [M+H]⁺=480.

[0928] C.7-[3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)2-oxopyrrolidin-1-ylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid benzyl ester

[0929] To a solution of7-(3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid benzyl ester (0.347 g, 0.72 mmol) in 8 mL of CH₂Cl₂ is added 2 mLof TFA. After 4 hours, the solution is concentrated. The residue isdissolve in CH₂Cl₂ and Et₃N (0.30 mL, 2.17 mmol) and 6-chlorobenzo[b]thiophene sulfonyl chloride (0.23 g, 0.87 mmol) are added. After16 hours, the solution is concentrated. The residue is purified bycolumn chromatography eluting with 10% EtOAc/CH₂Cl₂. The product (0.25g, 0.51 mmol) was obtained as a white solid.

[0930]¹H NMR (CDCl₃, 300 MHz) δ7.91 (s, 1H), 7.80 (m, 2H), 7.42 (d, 1H),7.34 (m, 5H), 7.08 (d, 1H), 6.96 (d, 1H), 6.88 (s, 1H), 5.10 (s, 2H),4.58 (s, 2H), 4.34 (s, 2H), 3.88 (m, 1H), 3.68 (m, 2H), 3.18 (m, 2H),2.77 (m, 2H), 2.59 (m, 1H), 2.08 (m, 1H).

[0931] D. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0932]7-[3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid benzyl ester (0.25 g, 0.51 mmol) is added to 5 mL of 30% HBr/AcOHat 0° C. The solution is stirred for 30 minutes. After this time, 30 mLof Et₂O is added. The resulting solid is collected by filtration. Thecrude solid is purified by RP-HPLC eluting with a gradient of 10%CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA). The appropriatefractions are lyophilized to provide the title compound as a whitesolid.

[0933]¹H NMR (DMSO-d₆, 300 MHz) δ8.95 (bs, 2H), 868 (d, 1H), 8.24 (s,1H), 8.00 (m, 2H), 7.51 (dd, 1H), 7.16 (d, 1H), 7.06 (m, 1H), 6.96 (s,1H) 4.27 (s, 2H), 4.16 (m, 3H), 3.30 (m, 2H), 3.05 (m, 2H), 2.92 (m,2H), 2.08 (m, 1H), 1.60 (m, 1H). FAB MS, [M+H]⁺=476, 478, chlorinepattern.

EXAMPLE 41

[0934] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-amide

[0935] A. 1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine

[0936] Benzenesulfonyl chloride (3 mL, 23.5 mmol) is added dropwise to asolution of tetrabutylammonium hydrogen sulfate (.0.53 g, 1.56 mmol),sodium hydroxide (1.56 g, 38.9 mmol) and4-chloro-1H-pyrrolo[3,2-c]pyridine (2.38 g, 15.6 mmol) (preparedaccording to Rasmussen, M. J. Het. Chem, 1992, 29, 359) in CH₂Cl₂. Themixture is stirred at room temperature for 4 hours the diluted withCH₂Cl₂ and washed with saturated NH₄Cl solution and brine. The organiclayer is dried over MgSO₄, filtered and concentrated. The crude productis purified by column chromatography eluting with 1% MeOH/CH₂Cl₂ to 2%MeOH/CH₂Cl₂ to afford the title product (3.21 g, 11 mmol) as a whitesolid.

[0937]¹H NMR (CDCl₃, 300 MHz) δ8.25 (d, 1H), 7.92(m, 1H), 7.90 (d, 1H),7.83 (dd, 1H), 7.60-7.66 (m, 2H), 7.51 (m, 2H), 6.80 (dd, 1H). EI MS,[M]⁺=292, 294, Cl pattern.

[0938] B.1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acidethyl ester

[0939] Lithium diisopropylamide (3.2 mL of a 1.5 M solution in THF, 4.80mmol) is added to a solution of tetramethylethylenediamine (0.71 mL,4.75 mmol) and 1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (1g, 3.42 mmol) in THF (13 mL). The resulting yellow solution is stirredat −78° C. for 1 hour, and then ethyl chloroformate (0.78 mL, 8.16 mmol)is added dropwise. The mixture is slowly brought to room temperatureover a 3.5 hour period. The reaction is quenched with saturated NH₄Clsolution and then diluted with ethyl acetate. The organic layer iswashed with brine, dried over MgSO₄, filtered and concentrated to give alight brown solid (1.46 g) as the product which is used in thesubsequent step without further purification.

[0940]¹H NMR(CDCl₃, 300 MHz) δ8.30 (d, 1H), 8.12 (d,2H), 8.03 (d, 1H),7.70(m, 1H), 7.55 (m,22H), 7.30(s, 1H). 4.45 (q, 2H), 1.46 (t, 3H). FABMS, [M+H]⁺=365, 367, Cl pattern.

[0941] C.1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)-methanol

[0942] Lithium aluminum hydride (3.4 mL of a 1 M solution in THF) isadded dropwise to a solution of the1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acidethyl ester (1.46 g, 3.42 mmol) in THF (27 mL) at 0° C. After stirringfor 1.5 hours at 0° C., the reaction is quenched with H₂O then dilutedwith ethyl acetate. The organic layer is washed with saturated NH₄Clsolution and brine then dried over MgSO₄, filtered and concentrated. Thecrude product is purified by column chromatography eluting with agradient of 1% MeOH/CH₂Cl₂ to 3% MeOH/CH₂Cl₂ to afford the title product( 0.78 g, 2.42 mmol) as a white solid.

[0943]¹H NMR (CDCl₃, 300 MHz) δ8.25 (d, 1H), 8.85-8.95 (m, 3H), 7.64 (m,1H), 7.51 (m, 2H), 6.80 (s, 1H), 4.97 (d, 2H), 2.85 (t, 1H). EI MS,[M]⁺=322, 324, Cl pattern.

[0944] D.1-Benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine

[0945] Carbon tetrabromide (0.939 g, 2.83 mmol) is added to a solutionof triphenylphosphine (1.485 g, 5.66 mmol) and1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)-methanol(0.914 g, 2.83 mmol) in CH₂Cl₂ (12 mL) at 0° C. The resulting yellowsolution is stirred for 1 hour at 0° C. then warmed to room temperatureover a 1 hour period. The reaction mixture is concentrated then purifiedby column chromatography eluting with 1% MeOH/CH₂Cl₂ to afford the titleproduct (0.760 g, 1.97 mmol) as a white solid.

[0946]¹H NMR (CDCl₃, 300 MHz) δ8.27 (d, 1H), 7.91-8.00 (m, 3H), 7.67 (m,1H), 7.51 (m, 2H), 6.95 (s, 1H), 4.94 (s, 2H). FAB MS, [M+H]⁺=385, 387,389, Br, Cl pattern.

[0947] E.[1-(1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolid-3-(S)-yl]-carbamicacid tert-butyl ester

[0948] Sodium hydride (0.081 g, 2.02 mmol, 60% mineral oil dispersion)is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acidtert-butyl ester (0.404 g, 2.02 mmol) in DMF (5 mL) at 0° C. The mixtureis stirred for 10 minutes, then cannulated dropwise to a solution of1-benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (0.74g, 1.92 mmol) in DMF (10 mL) at 0° C. The resulting yellow solution isstirred for 1 hour at 0° C. then quenched with saturated ammoniumchloride solution and diluted with EtOAc. The organic layer is washedwith water and brine, then dried over MgSO₄, filtered and concentrated.The solid product (0.94 g, 1.86 mmol) is used in the subsequent stepwithout further purification.

[0949]¹H NMR (CDCl₃, 300 MHz) δ8.25 (d, 1H), 7.98 (m, 2H), 7.83 (d, 1H),7.68 (m, 1H), 7.50 (m, 2H), 6.70 (s, 1H), 4.95 (AB, 2H), 4.20 (m, 1H),3.55 (m, 2H), 2.65 (m, 1H), 2.03 (m, 1H), 1.45 (s, 9H). FAB MS,[M+H]⁺=505, 507, Cl pattern.

[0950] F.3-(S)-Amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride

[0951] The title compound is prepared as described in EXAMPLE 1, Part Iusing[1-(1-benzenesulfonyl-4chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolid-3-(S)-yl]-carbamicacid tert-butyl ester in place of[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)yl]-carbamicacid tert-butyl ester and stirring for 2 hours at 0° C. without warmingto room temperature.

[0952]¹H NMR (CDCl₃, 300 MHz) δ8.50 (d, 1H), 8.28 (d, 1H), 8.04 (m, 2H),7.82 (m, 1H), 7.65 (m, 2H), 6.83 (s, 1H), 4.93 (s, 2H), 4.20 (m, 1H),3.51 (m, 2H), 2.41 (m, 1H), 2.01 (m, 1H). FAB MS, [M+H]⁺=405, 407, Clpattern.

[0953] G. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-benzenesulfonyl4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0954] The title compound is prepared as described in EXAMPLE 1, Part Kusing 6-chlorobenzo[b]thiophene-2-sulfonyl chloride and3-amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride as the starting material. The crude product is purified bycolumn chromatography eluting with a gradient of 1% MeOH/CH₂Cl₂ to 3%MeOH/CH₂Cl₂ to give the product as a while solid.

[0955]¹H NMR (CDCl₃, 300 MHz) δ8.23 (d, 1H), 7.96 (d, 1H), 7.90 (s, 1H),7.70-7.7.88 (m, 3 H), 7.55-7.61 (m, 2H), 7.40-7.50 (m, 3H), 6.51 (s,1H), 5.45 (bs, 1H), 4.86 (s, 2H), 3.98 (m, 1H), 3.41 (m, 2H), 2.70 (m,1H), 2.18 (m, 1H).

[0956] FAB MS, [M+H]⁺=635, 637, Cl pattern.

[0957] H. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0958] Ammonia gas is bubbled for 5 minutes into a solution of6-chlorobenzo[b]thiophene-2-sulfonicacid[1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(0.14 g, 0.22 mmol) in MeOH (10 mL). The solution is refluxed overnightthen concentrated to dryness. The crude product is purified by columnchromatography eluting with 5% MeOH/CH₂Cl₂ to give the product (0.065 g,0.13 mmol) as a white solid.

[0959]¹H NMR (DMSO-d₆, 300 MHz) δ11.95 (bs, 1H), 8.71 (d, 1H), 8.30 (s,1H), 8.05 (m, 1H), 7.91 (d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 6.40 (s,1H), 4.50 (AB, 2H), 4.23 (m, 1H), 3.23m, 2H), 2.41 (M, 11H), 1.78 (m,1H). Ion spray MS, [M+H]⁺=495, 497, Cl pattern.

EXAMPLE 42

[0960] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[0961] Palladium on carbon (0.01 g) is added to a solution of6-chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidein 95% ethanol (5 mL) and charged with H₂ gas. The mixture is heated at65° C. overnight then cooled to room temperature and filtered throughCelite. The solvent is removed and the crude product is purified byRP-HPLC eluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100%CH₃CN. The appropriate product fractions are lyophilized to give thetitle compound as a white solid.

[0962]¹H NMR (DMSO-d₆, 300 MHz) δ14.60 (bs, 1H), 12.70 (bs, 1H), 9.15(s, 1H), 8.71 (d, 1H), 8.38 (d, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 8.00(d, 1H), 7.85 (d, 1H), 7.52 (dd, 1H), 6.88 (s, 1H), 4.63 (AB, 2H), 4.21(m, 1H), 3.25 (m, 2H), 2.10 (m, 1H), 1.75 (m, 1H). Ion spray MS,[M+H]⁺=461, 463, Cl pattern.

EXAMPLE 43

[0963] 7-Methoxynaphthalene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0964] A. 5-Chloro-1H-pyrrolo[3,2-b]pyridine

[0965] A mixture of pyrrolo[3,2-b]pyrid-5-one (prepared according to theprocedure described in J. Med. Chem. 1990, 33, 2087) (1.33 g, 9.91 mmol)and 20 mL of phosphorous oxychloride is heated in a sealed Parr highpressure stainless steel vessel at 180° C. for 2.5 hours. After cooling,excess phosphorous oxychloride is removed in vacuo. The residue iscooled in an ice bath and quenched with ice water. The resulting mixtureis neutralized by addition of saturated NaHCO₃ solution and extractedwith EtOAc (3×). The combined organic layers are dried over MgSO₄,filtered and concentrated in vacuo. The crude product (1.07 g, 7.01mmol) is used in the subsequent step without further purification.

[0966]¹H NMR (CDCl₃+CD₃OD, 300 MHz) δ7.71 (d, 1H), 7.49 (d, 1H), 7.10(d, 1H), 6.59 (d, 1H). EI MS, [M]⁺=152, 154, Cl pattern.

[0967] B. 1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine

[0968] The title compound is prepared from5-chloro-1H-pyrrolo[3,2-b]pyridine as described in EXAMPLE 41, Part A.The crude product is purified by column chromatography eluting with agradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the titlecompound as a solid.

[0969]¹H NMR (CDCl₃, 300 MHz) δ8.23 (d, 1H), 7.87 (d, 2H), 7.81 (d, 1H),7.62 (m, 1H), 7.49 (m, 2H), 7.26 (d, 1H), 6.81 (d, 1H).

[0970] C.1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acidethyl ester

[0971] The title compound is prepared from1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine as described inEXAMPLE 41, Part B. The crude product is purified by columnchromatography eluting with a gradient of 10% EtOAc/hexanes to 33%EtOAc/hexanes to yield the title compound as a solid.

[0972]¹H NMR (CDCl₃, 300 MHz) δ8.41 (d, 1H), 8.04 (d, 2H), 7.66 (m, 1H),7.55 (m, 2H), 7.37 (d, 1H), 7.21 (s, 1H), 4.41 (q, 2H), 1.40 (t, 3H). EIMS, [M]⁺=364, 366, Cl pattern.

[0973] D.(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-methanol

[0974] The title compound is prepared from1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acidethyl ester as described in EXAMPLE 41, Part C. The crude product ispurified by column chromatography eluting with a gradient of 20%EtOAc/hexanes to 50% EtOAc/hexanes to afford the title compound as asolid.

[0975]¹H NMR (CDCl₃, 300 MHz) δ8.30 (d, 1H), 7.81 (d, 2H), 7.63 (m, 1H),7.50 (m, 2H), 7.25 (d, 1H), 6.80 (s, 1H), 4.97 (s, 2H), 2.99 (bs, 1H).EI MS, [M]⁺=322, 324, Cl pattern.

[0976] E.1-Benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine

[0977] To a solution of(1-benzenesulfonyl-5-chloro-1H-pyrrolop[3,2-b]pyridin-2-yl)-methanol(0.16 g, 0.50 mmol) in 4 mL Et₂O/CH₂Cl₂ (1:1) at 0° C. is addedphosphorous tribromide (0.023 mL, 0.25 mmol) dropwise. The reactionvessel is kept in the dark and stirred at 0° C. for 1 hour, then at roomtemperature for 2 hours. The mixture is diluted with water and EtOAc andthe layers are separated. The aqueous layer is extracted with EtOAc. Thecombined organic layers are washed with water, saturated NaHCO₃ solutionand saturated NaCl solution, then dried over MgSO₄, filtered andconcentrated. The crude product (0.16 g, 0.41 mmol) is used in thesubsequent step without further purification.

[0978]¹H NMR (CDCl₃, 300 MHz) δ8.33 (d, 1H), 7.87 (d, 2H), 7.64 (m, 1H),7.50 (m, 2H), 7.28 (d, 1H), 6.93 (s, 1H), 4.96 (s, 2H).

[0979] F. [1-(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester

[0980] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using1-benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine inplace of 7-bromomethyl-1-chloro-isoquinoline. The crude product ispurified by column chromatography eluting with a gradient of 15%EtOAc/hexanes to 50% EtOAc/hexanes to give the title compound as a beigesolid.

[0981]¹H NMR (CDCl₃, 300 MHz) δ8.36 (d, 1H), 7.80 (d, 2H), 7.64 (m, 1H),7.50 (m, 2H), 7.25 (s, 1H), 6.58 (s, 1H), 5.13 (bs, 1H), 4.93 (AB, 2H),4.22 (m, 1H), 3.39 (m, 2H), 2.66 (m, 1H), 1.95 (m, 1H), 1.46 (s, 9H).

[0982] G.3-(S)-Amino-1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride

[0983] The title compound is prepared as described in EXAMPLE 1, Part Iusing[1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid tert-butyl ester as the starting material. The title compound isobtained as a white solid.

[0984]¹H NMR (DMSO-d₆, 300 MHz) δ8.51 (bs, 2H), 8.42 (d, 1H), 8.00 (d,2H), 7.78 (m, 1H), 7.64 (m, 2H), 7.41 (d, 1H), 6.96 (s, 1H), 4.90 (AB,2H), 4.16 (m, 1H), 3.49 (m, 2H), 2.47 (m, 1H), 2.10 (m, 1H).

[0985] H. 7-Methoxynaphthalene-2-sulfonicacid[1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0986] The title compound is prepared as described in EXAMPLE 1, Part Kusing 7-methoxynaphthalene-2-sulfonyl chloride and3-(S)-amino-1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2onehydrochloride as starting material. The crude product is used in thesubsequent step without further purification.

[0987]¹H NMR (CDCl₃, 300 MHz) δ8.37 (s, 1H), 8.34 (d, 1H), 7.92 (d, 1H),7.79 (m, 2H), 7.72 (m, 2H), 7.58 (m, 1H), 7.45 (m, 2H), 7.31 (dd, 1H),7.24 (m, 2H), 6.48 (s, 1H), 5.42 (s, 1H), 4.85 (s, 2H), 3.96 (s, 3H),3.76 (m, 1H), 3.34 (m, 2H), 2.63 (m, 1H), 2.10 (m, 1H).

[0988] I. 7-Methoxynaphthalene-2-sulfonicacid[1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[0989] The title compound is prepared from7-methoxynaphthalene-2-sulfonicacid[1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideas described in EXAMPLE 41, Part H. The crude product is purified bycolumn chromatography eluting with a gradient of 1% MeOH/CH₂Cl₂ to 6%MeOH/CH₂Cl₂ to yield the title compound as a solid.

[0990]¹H NMR (CDCl₃, 300 MHz) δ9.73 (bs, 1H), 8.35 (s, 1H), 7.70 (m,3H), 7.49 (d, 1H), 7.30 (dd, 1H), 7.20 (m, 1H), 6.99 (d, 1H), 6.75 (bs,1H), 6.48 (s, 1H), 4.58 (m, 2H), 3.93 (m, 1H), 3.90 (s, 3H), 3.35 (m,2H), 2.48 (m, 1H), 2.08 (m, 1H).

[0991] J. 7-Methoxynaphthalene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[0992] The title compound is prepared from7-methoxynaphthalene-2-sulfonic acid[1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amideas described in EXAMPLE 42 at room temperature using a catalytic amountof KOH in MeOH/benzene (1:1) instead of EtOH solvent. The crude productis purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O (0.1% TFA)to 70% CH₃CN/H₂O (0.1% TFA) and the appropriate product fractions arelyophilized to provide the title compound as a white solid.

[0993]¹H NMR (DMSO-d₆, 300 MHz) δ12.65 (bs, 1H), 8.60 (bs, 1H), 8.43 (d,1H), 8.39 (s, 1H), 8.26 (d, 1H), 8.03. (d, 1H), 7.94 (d, 1H), 7.71 (dd,1H), 7.56 (m, 2H), 7.32 (dd, 1H), 6.80 (s, 1H), 4.66 (AB, 2H), 4.17 (m,1H), 3.88 (s, 3H), 3.20 (m, 2H), 2.00 (m, 1H), 1.60 (m, 1H). FAB MS,[M+H]⁺=451.

EXAMPLE 44

[0994] 6-Chloro-benzo[b]thiophene-2-sulfonic acid(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl-amide

[0995] A. (2-Oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acidtert-butyl ester

[0996] The title compound is prepared from(2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as describedin EXAMPLE 1, Part H using propargyl bromide in place of7-bromomethyl1-chloro-isoquinoline. The crude product is triturated fromEt₂O/hexanes to give the title compound as a white solid.

[0997]¹H NMR (CDCl₃, 300 MHz) δ5.09 (bs, 1H), 4.19 (m, 1H), 4.15 (m,2H), 3.45 (m, 2H), 2.69 (m, 1H), 2.29 (t, 1H), 1.91 (m, 1H), 1.48 (s,9H).

[0998] B.(1-Furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-carbamic acidtert-butyl ester

[0999] A mixture of 2-iodo-3-hydroxy-pyridine (0.44 g, 2 mmol),(2-oxo-1-prop2-ynyl-pyrrolidin-3-(S)-yl-carbamic acid tert-butyl ester(0.6 g, 2.5 mmol), bis(triphenylphosphine)-palladium(II) chloride(Pd(PPh₃)₂Cl₂) (50 mg), copper iodide (25 mg) and triethylamine (3 mL)in 3 mL of acetonitrile is heated in a sealed tube at 120° C. for 2hours. After cooling, the reaction mixture is diluted with water andEtOAc and the layers are separated. The aqueous layer is extracted withEtOAc. The combined organic layers are washed with water and saturatedNaCl solution, then dried over MgSO₄, filtered and concentrated. Thecrude product is purified by column chromatography eluting with agradient of 25% EtOAc/CH₂Cl₂ to 90% EtOAc/CH₂Cl₂ to yield the titlecompound as a white solid.

[1000]¹H NMR (CDCl₃, 300 MHz) δ8.53 (d, 1H), 7.72 (dd, 1H), 7.21 (dd,1H), 6.86 (s, 1H), 5.15 (bs, 1H), 4.69 (AB, 2H), 4.23 (m, 1H), 3.38 (m,2H), 2.66 (m, 1H), 1.91 (m, 1H), 1.45 (s, 9H).

[1001] C. 3-(S)-Amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride

[1002] The title compound is prepared as described in EXAMPLE 1, Part Iusing(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-carbamic acidtert-butyl ester as the starting material. The title compound isobtained as a tan solid.

[1003]¹H NMR (DMSO-d₆, 300 MHz) δ8.70 (bs, 2H), 8.65 (d, 1H), 8.35 (d,1H), 7.58 (dd, 1H), 7.28 (s, 1H), 4.77 (s, 2H), 4.10 (m, 1H), 3.47 (m,2H), 2.41 (m, 1H), 2.09 (m, 1H).

[1004] D. 6-Chloro-benzo[b]thiophene-2-sulfonic acid(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-amide

[1005] The title compound is prepared as described in EXAMPLE 1, Part Kusing 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material. The crude product is purified bycolumn chromatography eluting with a gradient of 25% EtOAc/CH₂Cl₂ to 90%EtOAc/CH₂Cl₂ to provide the title compound as a white solid.

[1006]¹H NMR (CDCl₃+CD₃OD, 300 MHz) δ8.49 (bs, 1H), 7.92 (s, 1H), 7.85(s, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.41 (dd, 1H), 7.24 (m, 1H), 6.85(s, 1H), 4.63 (AB, 2H), 4.03 (m, 1H), 3.41 (m, 2H), 2.63 (m, 1H), 2.16(m, 1H). FAB MS, [M+H]⁺=462, 464, Cl pattern.

EXAMPLE 45

[1007] 6-Chloro-benzo[b]thiophene-2-sulfonic acid(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-amide

[1008] A. 1-Fluoro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene

[1009] The title compound is prepared as described in EXAMPLE 9, Part Asubstituting 3-fluorothiophenol for 3-chlorothiophenol. The crudeproduct is purified by column chromatography eluting with a gradient ofhexanes to 10% EtOAc/hexanes to afford the title compound as an oil.

[1010]¹H NMR (CDCl₃, 300 MHz) δ7.21 (m, 1H), 7.09 (m, 2H), 6.82 (m, 2H),4.51 (m, 1H), 3.09 (s, 31H), 3.07 (s, 3H).

[1011] B. 6-Fluoro-benzo[b]thiophene

[1012] The title compound is prepared as described in EXAMPLE 9, Part Bsubstituting 1-fluoro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene for1-chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)benzene. The crude product ispurified by column chromatography eluting with hexanes to afford thetitle compound as a white solid. EI MS, [M]⁺=152.

[1013] C. 6-Fluoro-benzo[b]thiophene-2-sulfonyl chloride

[1014] The title compound is prepared as described in EXAMPLE 8, Part Asubstituting 6-fluoro-benzo[b]thiophene for thianaphthalene. The crudeproduct is purified by column chromatography eluting with hexanes toyield the title compound as a white solid.

[1015]¹H NMR (CDCl₃, 300 MHz) δ8.08 (s, 1H), 7.94 (dd, 1H), 7.58 (dd,1H), 7.23 (dt, 1H).

[1016] D. 6-Fluoro-benzo[b]thiophene-2-sulfonic acid(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl-amide

[1017] The title compound is prepared as described in EXAMPLE 1, Part Kusing 6-fluoro-benzo[b]thiophene-2-sulfonyl chloride and3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material. The crude product is purified bycolumn chromatography eluting with 66% EtOAc/CH₂Cl₂ to provide the titlecompound as a white solid.

[1018]¹H NMR (CDCl₃, 300 MHz) δ8.46 (m, 1H), 7.96 (s, 1H), 7.91 (m, 1H),7.77 (d, 1H), 7.58 (d, 1H), 7.44 (s, 1H), 7.29 (m, 2H), 6.86 (s, 1H),4.65 (s, 2H), 4.14 (m, 1H), 3.42 (m, 2H), 2.58 (m, 1H), 2.09 (m, 1H).FAB MS, [M+H]⁺=446.

EXAMPLE 46

[1019] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1020] A. 2-Iodo-3-nitro-pyridine

[1021] To a solution of 2-amino-3-nitro-pyridine (8 g, 57.5 mmol) in 60mL of 6 N HCl cooled to 0° C. is added dropwise a solution of sodiumnitrite (6.35 g, 92 mmol) in 40 mL of water. The mixture is stirred at0° C. for 1.5 hours. Then a solution of potassium iodide (22.9 g, 138mmol) in 40 mL of water is added dropwise to the yellow solution. Theresulting red mixture is stirred at 0° C. for 30 minutes and then heatedat 60° C. for 45 minutes. After cooling, the mixture is made basic bythe careful addition of 3 N NaOH. The aqueous layer is extracted withCH₂Cl₂ (4×) and the combined organic layers are washed with 1 N HCl,dilute Na₂SO₃ and water. The organic layer is dried over MgSO₄, filteredand concentrated in vacuo. The crude product (2.72 g, 10.9 mmol) is usedin the subsequent step without further purification.

[1022]¹H NMR (CDCl₃, 300 MHz) δ8.65 (d, 1H), 8.25 (dd, 1H), 7.48 (m,1H). IS MS, [M+H]⁺=251.

[1023] B. 3-Amino-2-iodo-pyridine

[1024] To a solution of 2-iodo-3-nitro-pyridine (2.72 g, 10.9 mmol) in10 mL of concentrated HCl is added dropwise a solution of tin(II)chloride dihydrate (10.3 g, 45.7 mmol) in 12 mL of concentrated HCl. Themixture is heated at 90° C. for 15 minutes. The resulting red mixture iscooled to 0° C. and stirred for 2 hours as a precipitate forms. Thesolid is filtered, dissolved in water and made basic by addition of 1 NNaOH. The aqueous layer is extracted with CH₂Cl₂ (4×) and the combinedorganic layers are dried over MgSO₄, filtered and concentrated in vacuo.The crude product (1.5 g, 6.82 mmol) is used in the subsequent stepwithout further purification.

[1025]¹H NMR (CDCl₃, 300 MHz) δ7.81 (m, 1H), 7.07 (m, 2H), 4.05 (bs,2H). IS MS, [M+H]⁺=221.

[1026] C. (2-Iodo-pyridin-3-yl)-carbamic acid ethyl ester

[1027] Ethyl chloroformate (0.91 mL, 9.5 mmol) is added to a solution of3-amino-2-iodo-pyridine (1.4 g, 6.36 mmol) in 15 mL of pyridine cooledat 0° C. The mixture is stirred at 0° C. for 2 hours and allowed to warmslowly to room temperature. At this time, excess pyridine is removed invacuo. The residue is diluted with EtOAc and washed with water, 1N HCland saturated NaHCO₃. The organic layer is dried over MgSO₄, filteredand concentrated in vacuo. The crude product is purified by columnchromatography eluting with 30% EtOAc/hexanes to give the title compound(1.2 g, 4.11 mmol) as a beige solid.

[1028]¹H NMR (CDCl₃, 300 MHz) δ8.51 (d, 1H), 8.07 (dd, 1H), 7.25 (dd,1H), 7.16 (bs, 1H), 4.28 (q, 2H), 1.38 (t, 3H).

[1029] D.2-(3-(S)-tert-Butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester

[1030] A mixture of (2-iodo-pyridin-3-yl)-carbamic acid ethyl ester (0.6g, 2.05 mmol), (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acidtert-butyl ester (0.49 g, 2.05 mmol), Pd(PPh₃)₂Cl₂ (72 mg), copperiodide (12 mg) and triethylamine (1.1 mL) in 4 mL of acetonitrile isheated in a sealed tube at 100° C. for 18 hours. After cooling, thereaction mixture is diluted with MeOH and filtered through a Celite pad.The filtrate is concentrated in vacuo. The residue is diluted with EtOAcand washed with water (4×). The combined aqueous layers are extractedwith EtOAc (2×). The combined organic layers are washed with water, thendried over MgSO₄, filtered and concentrated to yield the crudeintermediate coupled acetylene. IS MS, [M+H]⁺=403. The crude acetyleneintermediate is dissolved in 16 mL of DMF and treated with1,8-diaza-bicyclo[5.4.0]undec-7ene (DBU) (0.58 mL, 4.1 mmol). Themixture is heated at 60° C. for 2 hours. After cooling, the resultingmixture is diluted with water and EtOAc and the layers are separated.The organic layer is washed with water and then dried over MgSO₄,filtered and concentrated. The crude product is purified by columnchromatography eluting with 90% EtOAc/CH₂Cl₂ to yield the title compound(0.07 g, 0.22 mmol) as a beige solid.

[1031]¹H NMR (CDCl₃, 300 MHz) δ8.51 (d, 1H), 8.35 (d, 1H), 7.21 (dd,1H), 6.60 (s, 1H), 5.34 (bs, 1H), 4.95 (AB, 2H), 4.55 (q, 2H), 4.30 (m,1H), 3.48 (m, 2H), 2.70 (m, 1H), 2.05 (m, 1H), 1.50 (t, 3H), 1.46 (s,9H). IS MS, [M+H]⁺=403.

[1032] E.2-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester hydrochloride.

[1033] The title compound is prepared as described in EXAMPLE 1, Part Iusing2-(3-(S)tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester as the starting material. The title compound isobtained as a beige solid.

[1034]¹H NMR (DMSO-d₆, 300 MHz) δ8.70 (m, 1H), 8.58 (m, 4H), 7.50 (m,1H), 6.91 (s, 1H), 4.91 (m, 2H), 4.51 (q, 2H), 4.01 (m, 1H), 3.50 (m,2H), 2.48 (m, 1H), 2.10 (m, 1H), 1.43 (t, 3H).

[1035] F.2-[3-(S)-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester

[1036] The title compound is prepared as described in EXAMPLE 1, Part Kusing 6chloro-benzo[b]thiophene-2-sulfonyl chloride and2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester hydrochloride as starting material. The crude productis purified by column chromatography eluting with 60% EtOAc/CH₂Cl₂ toprovide the title compound as a solid.

[1037]¹H NMR (CDCl₃, 300 MHz) δ8.49 (d, 1H), 8.30 (d, 1H), 7.90 (s, 1H),7.78 (s, 1H), 7.75 (d, 1H), 7.48 (dd, 1H), 7.20 (dd, 1H), 6.88 (bs, 1H),6.49 (s, 1H), 4.81 (AB, 2H), 4.49 (q, 2H), 4.13 (m, 1H), 3.39 (m, 2H),2.61 (m, 1H), 2.13 (m, 1H), 1.45 (t, 3H).

[1038] G. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl-amidetrifluoroacetate

[1039] To a solution of2-[3-(S)-(6-chloro-benzo[b]thiophene-2-sulfonylamino)2-oxopyrrolidin-1-ylmethyl]-pyrrolo[3,2-b]pyridine-1-carboxylicacid ethyl ester (0.03 g, 0.06 mmol) in 3 mL of MeOH is added 4 drops of10 N NaOH solution. The mixture is stirred at room temperature for 1hour. The crude mixture is purified by RP-HPLC eluting in a gradient of10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriateproduct fractions are lyophilized to provide the title compound (0.015g, 0.026 mmol) as a white solid.

[1040]¹H NMR (DMSO-d₆, 300 MHz) δ8.72 (d, 1H), 8.58 (bs, 1H), 8.41 (d,1H), 8.27 (d, 1H), 8.05 (s, 1H), 8.02 (d, 1H), 7.55 (m, 2H), 6.69 (bs,1H), 4.68 (AB, 2H), 4.25 (m, 1H), 3.30 (m, 2H), 2.20 (m, 1H), 1.73 (m,1H). IS MS, [M+H]⁺=461, 463, Cl pattern. Elemental analysis calculatedwith 1.6 mol H₂O cal. C=43.76%, H=3.54%, N=9.28%, found C=43.76%,H=2.98%, N=8.95%.

EXAMPLE 47

[1041] 6-Chloro-benzo[b]thiophene-2-sulfonic acid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1042] A. 3-(S)-Amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride

[1043] The title compound is prepared as described in EXAMPLE 1, Part Iusing (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid tert-butylester as the starting material. The title compound is obtained as abeige solid.

[1044]¹H NMR (CDCl₃+DMSO-d₆, 300 MHz) δ8.75 (bs, 3H), 4.15 (AB, 2H),3.90 (m, 1H), 3.53 (m, 2H), 2.76 (t, 1H), 2.59 (m, 1H), 2.19 (m, 1H).

[1045] B. 6-Chloro-benzo[b]thiophene-2-sulfonic acid(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)amide

[1046] The title compound is prepared as described in EXAMPLE 1, Part Kusing 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as startingmaterial. The crude product is isolated as a beige foam and used in thesubsequent step without further purification.

[1047]¹H NMR (CDCl₃, 300 MHz) δ7.90 (s, 1H), 7.85 (s, 1H), 7.80 (d, 1H),7.41 (dd, 1H), 5.53 (bs, 1H), 4.11 (AB, 2H), 3.91 (m, 1H), 3.42 (m, 2H),2.70 (m, 1H), 2.27 (t, 1H), 2.15 (m, 1H).

[1048] C. (4-Iodo-pyridin-3-yl)-carbamic acid tert-butyl ester

[1049] To a solution of (pyridin-3-yl)-carbamic acid tert-butyl ester(prepared according to the procedure described in Tetrahedron Lett.1994, 35, 9003) (2.2 g, 11.3 mmol) in 20 mL of THF at −78° C. is addeddropwise t-BuLi (15.4 mL of a 1.7 M solution in pentane, 26 mmol). After15 minutes, the solution is warmed to −10° C. for 3 hours. The mixtureis cooled to −78° C. and a solution of iodine (5.7 g, 22.4 mmol) in 20mL of THF is added via syringe. The resulting mixture is stirred at −78°C. for 1 hour, then allowed to warm to room temperature and quenchedwith saturated NH₄Cl solution. The aqueous layer is extracted with EtOAc(2×). The combined organic layers are washed with 1 N HCl, water, diluteNa₂S₂0₃, saturated NaHCO₃ and saturated NaCl. The organic layer is thendried over MgSO₄, filtered and concentrated. The crude product ispurified by column chromatography eluting with a gradient of 5%EtOAc/CH₂Cl₂ to 20% EtOAc/CH₂Cl₂ to yield the title compound (1.3 g,4.06 mmol) as a brown solid.

[1050]¹H NMR (CDCl₃, 300 MHz) δ9.17 (s, 1H), 7.92 (d, 1H), 7.70 (d, 1H),6.69 (bs, 1H), 1.58 (s, 9H). EI MS, [M]⁺=320.

[1051] D.2-[3-(S)-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-pyrrolo[2,3-c]pyridine-1-carboxylicacid tert-butyl ester

[1052] A mixture of (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester(0.85 g, 2.65 mmol), 6-chloro-benzo[b]thiophene-2-sulfonic acid(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide (0.98 g, 2.65 mmol),Pd(PPh₃)₂Cl₂ (95 mg), copper iodide (18 mg) and triethylamine (1.45 mL)in 8 mL of DMF is heated at 100° C. for 1.5 hours. The reaction mixtureis cooled to 50° C. and DBU is added. The resulting mixture is heated at50° C. for 1.5 hours. After cooling, the crude mixture is diluted withEtOAc and washed with saturated NH₄Cl solution, water and saturatedNaCl. The organic layer is dried over MgSO₄, filtered and concentrated.The crude product is purified by column chromatography eluting with agradient of 1% MeOH/CH₂Cl₂ to 4% MeOH/CH₂Cl₂ to afford the titlecompound (0.73 g, 1.3 mmol) as a tan solid.

[1053]¹H NMR (CDCl₃, 300 MHz) δ9.28 (s, 1H), 8.38 (d, 1H), 7.88 (m, 2H),7.68 (d, 1H), 7.46 (m, 3H), 6.31 (s, 1H), 4.93 (AB, 2H), 4.00 (m, 1H),3.49 (m, 2H), 2.76 (m, 1H), 2.26 (m, 1H), 1.60 (s, 9H). IS MS, [M]⁺=561,563, Cl pattern.

[1054] E. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1055] The title compound is prepared from2-[3-(S)-(6-chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-pyrrolo[2,3-c]pyridine-1-carboxylicacid tert-butyl ester as described in EXAMPLE 27, Part C. The crudeproduct is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 80% CH₃CN/H₂O (0.1% TFA) and the appropriate productfractions are lyophilized to provide the title compound as a whitesolid.

[1056]¹H NMR (DMSO-d₆, 300 MHz) δ13.07 (bs, 1H), 9.07 (s, 1H), 8.74 (d,1H), 8.29 (s, 1H), 8.27 (d, 1H), 8.03 (m, 311), 7.52 (dd, 1H), 6.79 (s,1H), 4.71 (AB, 2H), 4.27 (m, 1H), 3.29 (m, 2H), 2.20 (m, 1H), 1.77 (m,1H). FAB MS, [M+H]⁺=461, 463, Cl pattern. Elemental analysis calculatedwith 0.7 mol H₂O cal. C=44.94%, H=3.33%, N=9.53%, found C=44.92%,H=2.91%, N=8.91%.

EXAMPLE 48

[1057] Thieno[3,2-b]pyridine-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amideditrifluoroacetate

[1058] A. Thieno[3,2-b]pyridine-2-sulfonyl chloride

[1059] The title compound is prepared as described in EXAMPLE 8, Part Ausing thieno[3,2-b]pyridine (prepared according to the proceduredescribed in J. Heterocyclic Chem. 1984, 21, 785) in place ofthianaphthalene. The crude product is used in the subsequent stepwithout further purification.

[1060]¹H NMR (CDCl₃, 300 MHz) δ8.93 (dd, 1H), 8.39 (s, 1H), 8.38 (d,1H), 7.59 (m, 1H). EI MS, [M]⁺=233, 235, Cl pattern.

[1061] B. Thieno[3,2-b]pyridine-2-sulfonic acid(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide

[1062] The title compound is prepared as described in EXAMPLE 1, Part Kusing thieno[3,2-b]pyridine-2-sulfonyl chloride and3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as startingmaterial. The crude product is isolated as a white solid and used in thesubsequent step without further purification.

[1063]¹H NMR (CDCl₃, 300 MHz) δ8.81 (d, 1H), 8.22 (d, 1H), 8.13 (s, 1H),7.41 (m, 1H), 6.05 (bs, 1H), 4.10 (AB, 2H), 3.98 (m, 1H), 3.48 (m, 2H),2.70 (m, 1H), 2.27 (t, 1H), 2.17 (m, 1H).

[1064] C. Thieno[3,2-b]pyridine-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amideditrifluoroacetate

[1065] The title compound is prepared fromthieno[3,2-b]pyridine-2-sulfonic acid (2-oxo-I-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide as described in EXAMPLE 47, PartD. The crude mixture is diluted with EtOAc and washed with saturatedNH₄Cl solution, water and saturated NaCl. The aqueous layer isconcentrated in vacuo to a residue. The mixture of salts is trituratedwith MeOH and CH₂Cl₂, filtered, washed with CH₂Cl₂/MeOH and the yellowfiltrate is concentrated. The crude product is purified by RP-HPLCeluting in a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 50% CH₃CN/H₂O (0.1%TFA) and the appropriate product fractions are lyophilized to providethe title compound as a beige solid.

[1066]¹H NMR (DMSO-d₆, 300 MHz) δ13.00 (bs, 1H), 9.06 (s, 1H), 8.88 (d,1H), 8.77 (m, 1H), 8.60 (d, 1H), 8.26 (d, 1H), 8.12 (s, 1H), 8.01 (d,1H), 7.52 (m, 1H), 6.80 (s, 1H), 4.71 (AB, 2H), 4.35 (m, 1H), 3.30 (m,2H), 2.22 (m, 1H), 1.78 (m, 1H). IS MS, [M+H]⁺=428. Elemental analysiscalculated with 1.9 mol H₂O cal. C=40.05%, H=3.33%, N=10.15%, foundC=40.06%, H=2.82%, N=9.87%.

EXAMPLE 49

[1067] Benzo[b]thiophene-2-sulfonic acid(2-oxo-1-thieno[3,2-c]pyridin-2-ylmethyl-pyrrolidin-3-(S)-yl)-amidetrifluoroacetate

[1068] A.1-(Thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester

[1069] To a solution of1-(4-chlorothieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester (0.46 g, 1.2 mmol), prepared as described inEXAMPLE 33, Part F, in 20 mL of MeOH is added 10% by weight Pd/C (0.1 g)and KOH (0.13 g, 2.4 mmol). The atmosphere above the reaction isreplaced by hydrogen and the solution is heated to 50° C. After 16hours, the solution is filtered through Celite and the Celite is washedwith MeOH. The crude material is purified by column chromatographyeluting with a gradient of 30% EtOAc/CH₂Cl₂ to 40% EtOAc/CH₂Cl₂ to givethe product as a white solid (0.2 g, 0.7 mmol).

[1070]¹H NMR (CDCl₃, 300 MHz) δ9.00 (s, 1H), 8.44 (d, 1H), 7.70 (s, 1H),7.31 (s, 1H), 5.12 (bs, 1H), 4.72 (AB, 2H), 4.18 (m, 1H), 3.32 (m, 2H),2.62 (m, 1H), 1.88 (m, 1H), 1.42 (s, 9H). FAB MS, [M+H]⁺=348.

[1071] B. Benzo[b]thiophene-2-sulfonic acid(2-oxo-1-thieno[3,2-c]pyridin-2-ylmethyl-pyrrolidin-3-(S)-yl)-amidetrifluoroacetate

[1072] To a solution of1-(thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester (0.1 g, 0.35 mmol) in 4 mL of CH₂Cl₂ is added Et₃N(0.08 g, 0.78 mmol) and benzo[b]thiophene sulfonyl chloride (0.08g, 0.35mmol). After 6 hours, the solution is diluted with CH₂Cl₂ and washedwith 10% Na₂CO₃ and saturated NaCl. The residue is purified by RP-HPLCeluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 80% CH₃CN/H₂O(0.1% TFA). The appropriate fractions are lyophilized to provide thetitle compound as a white solid.

[1073]¹H NMR (DMSO-d₆, 300 MHz) δ9.25 (bs, 1H), 8.63 (d, 1H), 8.50 (m,1H), 8.39 (m, 1H), 7.99 (m, 4H), 7.61 (s, 1H), 7.46 (m, 2H), 4.70 (s,2H), 4.14 (m, 1H), 3.11 (m, 2H), 2.08 (m, 1H), 1.62(m, 1H). FAB MS,[M+H]⁺=444.

EXAMPLE 50

[1074] 7-Methoxynaphthalene-2-sulfonicacid[1-(1H-imidazo[4,5-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1075] A. [3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl esterhydrochloride

[1076] Sodium hydride (0.13 g, 3.3 mmol, 60% by weight) is added to asolution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester(0.6 g, 3 mmol) in THF (30 mL) at 0° C. The mixture is stirred for 30minutes then benzyl 2-bromo-acetate (0.76 g, 3.3 mmol) is added. Theresulting solution is warmed to room temperature and stirred for 1.5hours. The reaction mixture is quenched with saturated ammonium chloridesolution then diluted with methylene chloride. The organic layer isseparated, washed with brine, dried over MgSO₄, filtered andconcentrated. The residue is purified by flash chromatography (0-3%MeOH/CH₂Cl₂) and the material isolated is treated in ethyl acetate withHCl gas (as described in EXAMPLE 1, Part I) to give the title compound(0.55 g, 1.9 mmol) as a pale yellow solid.

[1077]¹H NMR (CD₃OD, 300 MHz) δ7.32 (m, 5H), 5.17 (s, 2H), 4.15 (d, 2H),4.08 (m, 1H), 3.54 (m, 2H), 2.54 (m, 1H), 2.03 (m, 1H). EI MS, [M]⁺=248.

[1078] B.3-(S)-(7-Methoxy-naphthalene-2-sulfonylamino)2-oxopyrrolidin-1-yl]-aceticacid

[1079] [3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl esterhydrochloride (0.34 g, 1.2 mmol) is suspended in CH₃CN (20 mL). To thismixture is added triethylamine (0.36 g, 3.6 mmol) followed by7-methoxy-naphthalene-2-sulfonyl chloride (0.31 g, 1.2 mmol). Themixture is stirred overnight at room temperature, subjected to aqueouswork up then concentrated to dryness. The crude material is purified byflash chromatography (0-5% MeOH/CH₂Cl₂). Subsequent hydrogenolysis inMeOH/CH₂Cl₂ with 5% Pd/C at 25 psi for 1.5 hours gave the title compound(0.40 g, 1 mmol) as a white solid.

[1080]¹H NMR (CDCl₃, 300 MHz) δ8.33 (S, 1H), 7.80 (m, 3H), 7.23 (m, 2H),5.90 (br, 1H), 3.95 (m, 6H), 3.38 (m, 2H), 2.40 (m, 1H), 2.07 (m, 1H).Ion Spray MS, [M+H]⁺=379.

[1081] C.N-(3-Amino-pyridin-4-yl)-2-[3-(S)-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-yl]-acetamide

[1082] Triethylamine (0.13 g, 1.3 mmol) and isobutyl chloroformate (0.18g, 1.3 mmol) are added to a solution of[3-(S)-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-yl]-aceticacid (0.5 g, 1.3 mmol) in THF (15 mL) at −10° C. The mixture is stirredfor 20 minutes then treated with a solution of 3,4-diamino-pyridine(0.16 g, 1.5 mmol) in DMF (5 mL). The resulting mixture is warmed toroom temperature and stirred for 3 hours. T he reaction mixture isconcentrated in vacuo, then diluted with methylene chloride. The organiclayer is washed with brine, dried over MgSO₄, filtered and concentrated.The residue is purified by flash chromatography (5-8% MeOH/CH₂Cl₂). togive the title compound (0.27 g, 0.58 mmol) as a solid.

[1083]¹H NMR (CDCl₃, 300 MHz) δ8.88 (br, 1H), 8.30 (s, 1H), 8.00 (s,1H), 7.85 (d, 1H), 7.70 (m, 3H), 7.40 (d, 1H), 7.20 (d, 1H), 7.12 (s,1H), 5.28 (s, 2H), 4.07 (m, 4H), 3.88 (3, 3H), 3.34 (m, 2H), 2.22 (m,1H), 1.90 (m, 1H). Ion Spray MS, [M+H]⁺=470.

[1084] D. 7-Methoxy-naphthalene-2-sulfonicacid[1-(1H-imidazor[4,5-c]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1085]N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-yl]-acetamide(0.22 g, 0.47 mmol) in acetic acid (15 mL) is heated at 110° C.overnight. The resulting solution is concentrated to dryness. Theresidue is purified by HPLC eluting with a gradient of 10 to 100%CH₃CN/0.1% TFA in water over 30 minutes. Fractions containing pureproduct are lyophilized to give the title compound as a white solid(0.24 g, 0.42 mmol).

[1086]¹H NMR (CDCl₃, 300 MHz) δ9.30 (s, 1H), 8.40 (d, 1H), 8.28 (s, 1H),7.95 (d, 1H), 7.70 (m, 3H), 7.40 (m, 1H), 7.20 (m, 2H), 7.14 (s, 1H),4.92 (m, 2H), 4.46 (m, 1H), 3.82 (s, 3H), 3.38 (m, 2H), 2.20 (m, 1H),2.03 (m, 1H). Ion Spray MS, [M+H]⁺=452.

EXAMPLE 51

[1087] 7-Methoxynaphthalene-2-sulfonicacid[1-(2-amino-3H-benzoimidazol-5-methyl)2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1088] A. 7-Methoxynaphthalene-2-sulfonicacid[1-(3,4-diaminobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[1089] 10% Palladium on carbon (0.08 g) is added to a solution of7-methoxy-naphthalene-2-sulfonicacid[1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.22 g,0.5 mmol) (prepared as described in EXAMPLE 25, Part F) in MeOH (40 mL)and CHCl₃ (3 mL) under nitrogen atmosphere. The heterogeneous mixture ishydrogenated at room temperature on a Parr apparatus under 47 p.s.i. ofhydrogen for 5 hours. The catalyst is filtered and the filtrate checkedby tlc shows no starting material. The filtrate is concentrated in vacuoand used in the subsequent step without further purification.

[1090]¹H NMR (CD₃OD, 300 MHz) δ8.41 (s, 1H), 7.93 (d, 1H), 7.85 (d, 1H),7.73 (d, 1H), 7.39 (d, 1H), 7.25 (dd, 1H), 7.02 (d, 1H), 6.89 (s, 1H),6.79 (dd, 1H), 4.30 (s, 2H), 4.13 (t, 1H), 3.95 (s, 3H), 3.13 (m, 2H),2.14 (m, 1H), 1.70 (m, 1H). Ion Spray MS, [M+H]⁺=441.

[1091] B. 7-Methoxynaphthalene-2-sulfonicacid[1-(2-amino-3H-benzoimidazol-5-methyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1092] Triethylamine (0.063 mL, 0.45 mmol) is added to a solution of7-methoxynaphthalene-2-sulfonicacid[1-(3,4-diaminobenzyl)2-oxopyrrolidin-3-(S)-yl]-amide (0.205 g, 0.47mmol) in MeOH (8 mL) under nitrogen. Cyanogen bromide (0.19 mL of a 3 Msolution, 0.56 mmol) is added dropwise to the reaction mixture at 0° C.After stirring for 5 minutes at 0° C., the reaction is brought to roomtemperature and stirred overnight. The clear solution is thenconcentrated in vacuo and the crude residue purified using columnchromatography eluting with a gradient of 9% MeOH/CH₂Cl₂ to 50%MeOH/CH₂Cl₂ to provide the product in 56% yield. The product islyophilized in acetonitrile/TFA-water to give the title compound as anoff-white solid.

[1093]¹H NMR (CD₃OD, 300 MHz) δ8.40 (d, 1H), 7.90 (d, 1H), 7.81 (d, 1H),7.75 (d, 1H), 7.36 (d, 1H), 7.25 (dd, 1H), 7.15 (d, 1H), 7.11 (d, 1H),6.92 (dd, 1H), 4.41 (AB, 2H), 4.15 (t, 1H), 3.91 (s, 3H), 3.10 (m, 2H),2.10 (m, 1H), 1.64 (m, 1H). Ion Spray MS, [M+H]⁺=466.

EXAMPLE 52

[1094] 3-(S)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride

[1095] A. 7-Methyl-1-phenoxyisoquinoline

[1096] The title compound is prepared as described in Example I, Part Lusing 1-chloro-7-methylisoquinoline as the starting material. The crudematerial is purified by column chromatography eluting with 20%EtOAc/hexanes to afford the title product as a pale yellow oil.

[1097]¹H NMR (CDCl₃, 300 MHz) δ8.22 (s,1H), 7.90 (d,1H), 7.68-7.60 (m,1H), 7.60-7.52 (m, 1H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 4H), 2.57 (s,3H).

[1098] B. 7-Bromomethyl-1-phenoxyisoquinoline

[1099] The title compound is prepared as described in Example 1, Part Fusing 7-methyl-1-phenoxyisoquinoline as the starting material. The crudeproduct is purified by column chromatography eluting with 10%EtOAc/hexanes to afford the title product as a clear oil.

[1100]¹H NMR (CDCl₃, 300 MHz) δ8.40 (s, 1H), 7.95 (d, 1H), 7.80-7.65 (m,2H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 4H), 4.65 (s, 2H).

[1101] C.[1-(1-Phenoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid benzyl ester

[1102] The title compound is prepared as described in Example 1, Part Husing 7-bromomethyl-1-phenoxyisoquinoline and[2-oxopyrrolidin-3-(S)-yl]carbamic acid benzyl ester as the startingmaterials. The crude product is purified by column chromatographyeluting with 70% EtOAc/hexanes to afford the title product as a clearoil.

[1103]¹H NMR (CDCl₃, 300 MHz) δ8.25 (s, 1H), 7.97 (d, 1H), 7.79 (d, 1H),7.60(d, 1H), 7.48-7.40 ( m, 2H), 7.38-7.20 (m, 9H), 5.40 (bs, 1H), 5.15(s, 2H), 4.75 (AB, 2H), 4.30 (m, 1H), 3.30 (m, 2H), 2.67 (m, 1H), 1.90(m, 1H).

[1104] D.[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid benzyl ester

[1105] The title compound is prepared as described in Example 1, Part Musing[1-(1-phenoxyisoquinolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-carbamicacid benzyl ester as the starting material. The reaction mixture isdiluted with methylene chloride and washed with 3 N NaOH and brine. Theorganic layer is dried over MgSO_(r), filtered and concentrated invacuo. The crude product is purified by column chromatography elutingwith 10% MeOH/CH₂Cl₂ to afford the title product as a foamy yellowsolid.

[1106]¹H NMR (CDCl₃, 300 MHz) δ7.95-7.87 (m, 2H), 7.70 (d, 1H), 7.45 (d,1H), 7.40-7.30 (m, SH), 7.00 (d, 1H), 5.75-5.55 (m, 3H), 5.20-5.15 (m,4H), 4.3-4.1 (m, 1H), 3.25 (m, 2H), 2.55 (m, 1H), 2.27 (m, 1H).

[1107] E. 3-(S)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride

[1108] 10% Palladium on carbon (0.089 g) is added to a solution of[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamicacid benzyl ester (0.33 g, 0.84 mmol) in ethanol. The heterogeneousmixture is hydrogenated at room temperature on a Parr apparatus under 45p.s.i. of hydrogen for 3 hours. The reaction mixture is filtered througha pad of Celite, washed with ethanol and the filtrate is concentrated invacuo to give the product (0.2 g, 0.78 mmol) as a foamy solid. Theproduct is dissolved in diethyl ether and cooled to 0° C. Hydrogenchloride gas is bubbled through the solution to yield the product as ahydrochloride salt.

[1109]¹H NMR (DMSO-d₆, 300 MHz) δ8.95-8.50 (b, 2H), 8.05 (s, 1H),7.75-7.70 (m, 2H), 7.53 (d, 1H), 7.30-7.10 (b, 2H), 6.93 (d, 1H), 4.57(AB, 2H), 3.40 (m, 1H), 3.15 (m, 1H), 2.37 (m, 1H), 2.02 (m, 1H). FABMS: [M+H]⁺=257.

[1110] F. 7-Methoxynapthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxo-pyolidin-3-(S)-yl]-amidetrifluoroacetate

[1111] The title compound can be prepared by an alternative route using3-(S)-amino-1-(1-aminoisoquinolin -7-ylmethyl)-pyrrolidin-2-onehydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as thestarting material and proceeding as described in Example 1, Part K.

EXAMPLE 53

[1112] 6-Chlorothieno[2,3-b]pyridine-2-sulfonyl chloride

[1113] A. 2-Bromo-6-chlorothieno[2,3-b]pyridine

[1114] The title compound is prepared from 2-bromo-5-acetyl thiopheneaccording to the procedure described in J. Chem. Soc., Perkin Trans. I,1981, 1531. The crude product is purified by column chromatographyeluting with 2% EtOAc/hexanes to afford a white solid.

[1115]¹HNMR (CDCl3, 300 MHz) δ7.89 (d, 1H), 7.28 (d, 1H), 7.27 (d, 1H).

[1116] B. 6-Chlorothieno[2,3-b]pyridine-2-sulfonyl chloride

[1117] The title compound is prepared as described in EXAMPLE 1, Part Dusing 2-bromo-6-chlorothieno[2,3-b]pyridine in place of thianaphthalene.The crude product is obtained as a white solid and is of sufficientpurity to be used in the subsequent step.

[1118]¹H NMR (CDCl3, 300 MHz) δ8.22 (d, 1H), 8.09 (s, 1H), 7.52 (d, 1H).EI MS, [M]+=267, 269, Cl pattern.

EXAMPLE 54

[1119] 6-Fluorobenzo[b]thiophene-2-sulfonyl chloride

[1120] The title compound is prepared as described in EXAMPLE 9, PartsA-C using 3-fluorothiophenol in place of 3-chlorothiophenol.

EXAMPLE 55

[1121] 6-Chlorothieno[3,2-b]pyridine-2-sulfonyl chloride

[1122] The title compound is prepared as described in EXAMPLE 48, Part Ausing 6-chlorothieno[3,2-b]pyridine (prepared according to the proceduredescribed in J. Heterocyclic Chem. 1984, 21, 785) in place ofthianaphthalene. The crude product is used in the subsequent stepwithout further purification.

[1123] Other compounds prepared according to the procedures aboveinclude those encompassed by the following formula:

[1124] wherein

[1125] is selected from the group of formulae consisting of

[1126] R₁, X₅, W and A are as defined herein; and R₂ is selected fromthe group of formulae consisting of

EXAMPLE 56

[1127] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1128] A. Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[1129] To a solution of3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (0.15 g, 0.48 mmol) suspended in CH₃CN (2.5 mL) is addedtriethylamine (0.23 mL, 1.6 mmol) followed bythieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). Themixture is stirred overnight, then concentrated. The residue is dilutedwith CH₂Cl₂ and washed with saturated NaHCO₃ and brine. The organiclayer is dried over MgSO₄, filtered and concentrated to dryness. Thecrude product is purified by column chromatography eluting with 5%MeOH/CH₂Cl₂to give the title compound (0.076 g, 0.16 mmol) as a lightyellow solid.

[1130]¹H NMR (CDCl₃, 300 MHz) δ8.85 (d, 1H), 8.32 (d, 1H), 8.27 (d, 1H),8.15 (s, 2H), 7.85 (d, 1H), 7.58-7.65 (m, 2H), 7.45 (dd, 1H), 5.60 (bs,1H), 4.68 (AB, 2H), 4.00 (m, 1H), 3.31 (m, 2H), 2.72 (m, 1H), 2.20 (m,1H). EI MS, [M.]⁺=472.

[1131] B. Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1132] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide(1.36 g, 2.88 mmol) and phenol (2.22 g, 23.6 mmol) are melted togetherwith stirring at 70° C. for 5 minutes. Ammonium acetate (2.71 g, 28.8mmol) is added and the reaction mixture is heated to 90° C. and stirredovernight. Additional ammonium acetate (0.50 g, 5.31 mmol) is added andthe reaction is heated for 20 more hours. The reaction is cooled and theresidue is purified by RP-HPLC eluting in a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate product fractions arelyophilized to provide the title compound as a white solid. Theenantiomeric purity is 90.5% ee as determined by analytical Chiralpak ASRP-HPLC.

[1133]¹H NMR (DMSO-d₆, 300 MHz) δ12.90 (bs, 1H), 9.00 (bs, 1H), 8.88 (d,1H), 8.79 (dd, 1H), 8.60 (dd, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.95 (d,1H), 7.79 (dd, 1H), 7.65 (d, 1H), 7.53 (dd, 1H), 7.23 (d, 1H), 4.50 (AB,2H), 4.38 (m, 1H), 3.21 (m, 2H), 2.20 (m, 1H), 1.81 (m, 1H). Ion Spray,[M+H]⁺=454.

EXAMPLE 57

[1134] Thieno[2,3-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl1)2-oxo-pyrrolidin-3-(S)-yl]-amide

[1135] A. Thieno[2,3-b]pyridine-2-sulfonyl chloride

[1136] n-Butyl lithium (6.0 mL of a 1.6 M solution in hexanes, 9.6 mmol)is added to a solution of thieno[2,3-b]pyridine (1.18 g, 8.7 mmol) (J.Org. Chem. 1969, 34(2), 347) in THF (30 mL) at −78° C. After 40 min.,the solution is added to a precooled (−78° C.) solution of SO₂ (ca. 6mL) in Et₂O (30 mL) via cannula. After addition, the solution is stirredfor 30 min. then allowed to warm to ambient temperatures. After 2 h, thesolution is concentrated to give a brown solid. The residue is suspendedin hexanes (30 mL) and SO₂Cl₂ (0.6 mL, 7.5 mmol) is added dropwise atroom temperature. After stirring for I h, the solution is concentratedthen diluted with methylene chloride and saturated NaHCO₃ solution. Theorganic layer is separated and dried over MgSO₄, filtered andconcentrated. The crude product is purified by column chromatographyeluting with 20% EtOAc/hexanes to give a white solid as the titleproduct.

[1137]¹H NMR (CDCl₃, 300 MHz) δ8.81 (dd, 1H), 8.30 (dd, 1H), 8.12 (s,1H), 7.50 (dd, 1H). EI MS, [M.]⁺=233, 235, Cl pattern.

[1138] B. Thieno[2,3-b]pyridine-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1139] The title compound is prepared as described in EXAMPLE 56, Part Ausing thieno[2,3-b]pyridine-2-sulfonyl chloride and3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material. The crude product is purified bycolumn chromatography eluting with 5% MeOH/CH₂Cl₂to give the titlecompound as a white solid.

[1140]¹H NMR (CDCl₃, 300 MHz) δ8.72 (dd, 1H), 8.31 (d, 1H), 8.22 (dd,1H), 8.13 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H), 7.60 (d, 1H), 7.58 (d,1H), 7.43 (dd, 1H), 5.89 (d, If), 4.70 (AB, 2H), 4.05 (m, 1H), 3.31 (m,2H), 2.68 (m, 1H), 2.13 (m, 1H). Ion Spray, [M+H]⁺=473, 475, Cl pattern.

[1141] C. Thieno[2,3-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide

[1142] The title compound is prepared as described in EXAMPLE 56, Part Busing thieno[2,3-b]pyridine-2-sulfonicacid[-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-S-)yl]-amideas starting material. The crude product is purified by RP-HPLC elutingwith a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. Theappropriate fractions are lyophilized to provide the title compound as awhite solid.

[1143]¹H NMR (DMSO-d₆, 300 MHz) δ12.90 (bs, 1H), 9.00 (bs, 1H), 8.80 (d,1H), 8.72 (dd, 1H), 8.42 (dd, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.95 (d,1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.58 (dd, 1H), 7.21 (d, 1H), 4.50 (AB,2H), 4.35 (m, 1H), 3.25 (m, 2H), 2.21 (m, 1H), 1.80 (m, I11). Ion Spray,[M+H]⁺=454.

EXAMPLE 58

[1144] 4-Pyridin-3-yl-thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3)-yl]-amide

[1145] A. 4-Pyridin-3-yl-thiophene-2-sulfonyl chloride

[1146] The title compound is prepared as described in EXAMPLE 57, Part Ausing 2-bromo-4-pyridin-3-yl-thiophene (J. Het. Chem. 1995, 32, 435) inplace of thieno[2,3-b]pyridine and performing the reaction at −100° C.rather than at −78° C. The crude product is purified by columnchromatography eluting with a gradient of 10% EtOAc/hexanes to 20%EtOAc/hexanes to give a pale yellow solid.

[1147]¹H NMR (CDCl₃, 300 MHz) δ8.87 (dd, 1H), 8.65 (dd, 1H), 8.3 (d,1H), 7.98 (d, 1H), 7.90 (m, 1H), 7.42 (m, 1H). EI MS, [M.]⁺=259, 261, Clpattern.

[1148] B. 4-Pyridin-3-yl-thiophene-2-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1149] The title compound is prepared as described in EXAMPLE 56, Part Ausing 4-pyridin-3-yl-thiophene-2-sulfonyl chloride and3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material. The crude product is purified bycolumn chromatography eluting with a gradient of 2% MeOH/CH₂Cl₂to 4%MeOH/CH₂Cl₂ to give the title compound as a white solid.

[1150]¹H NMR (CDCl₃, 300 MHz) δ8.88 (d, 1H), 8.60 (dd, 1H), 8.31 (d,1H), 8.14 (s, 1H), 7.95 (d, 1H), 7.88 (m, 1H), 7.82 (d, 1H), 7.79 (d,1H), 7.55-7.60 (m, 2H), 7.38 (m, 1H), 5.45 (d, 1H), 4.63 (AB, 2H), 3.95(m, 1H), 3.29 (m, 2H), 2.68 (m, 1H), 2.14 (m, 1H), 1.6 (s, 9H). IonSpray, [M+H.]⁺=499, 501.

[1151] C. 4-Pyridin-3-yl-thiophene-2-sulfonicacid[-1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1152] The title compound is prepared as described in EXAMPLE 56, Part Busing 4-pyridin-3-yl-thiophene-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amideas starting material. The crude product is purified by RP-HPLC elutingwith a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. Theappropriate fractions are lyophilized to provide the title compound as awhite solid.

[1153]¹H NMR (DMSO-d₆, 300 MHz) δ12.98 (bs, 1H), 9.00 (bs, 2H),8.48-8.57 (m, 2H), 8.39 (s, 1H), 8.27 (s, 1H), 8.15-8.21 (m, 2H), 7.92(d, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.48 (m, 1H), 7.21 (d, 1H), 4.56(AB, 2H), 4.39 (m, 1H), 3.20 (m, 2H), 2.20 (m, 1H), 1.73 (m, 1H). IonSpray, [M+H.]⁺=480.

EXAMPLE 59

[1154] 5′Chloro-[2,2′]bithiophenyl-5-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide

[1155] A. 4-Amino-3-iodo-pyridine

[1156] A solution of potassium iodide (19.48 g, 117.4 mmol) and iodine(18.37 g, 72.3 mmol) in water (77 mL) is added dropwise via an additionfunnel to a refluxing solution of 4-aminopyridine (9.21 g, 97.8 mmol)and sodium carbonate (6.12 g, 57.7 mmol) in water (35 mL). Upon completeaddition the mixture is stirred for 2 h at reflux then cooled to roomtemperature and extracted with ethyl acetate. The combined organiclayers are washed with saturated sodium thiosulfate solution (×3) andbrine then dried over MgSO₄, filtered and concentrated to give the titleproduct (8.37 g, 38.0 mmol) and a trace of the di-iodo compound as anyellow/orange solid. This material was used in the subsequent stepwithout further purification.

[1157]¹H NMR (CDCl₃, 300 MHz) δ8.70 (s, 1H), 8.10 (d, 1H), 6.55 (d, 1H),4.60 (bs, 2H).

[1158] B. (3-lodo-pyridin-4-yl)-carbamic acid tert-butyl ester

[1159] Di-tert-butyl dicarbonate (20.7 g, 94.8 mmol) is added to asolution of 4amino-3-iodo-pyridine (19.0 g, 86.4 mmol) in THF (86 mL).The resulting solution is stirred for 2 h at room temperature thenconcentrated to dryness. The residue is diluted with ethyl acetate andwashed with saturated sodium bicarbonate solution and brine. The organiclayer is dried over MgSO₄, filtered and concentrated to dryness. Theresidue is purified by column chromatography eluting with 1%EtOAc/CH₂Cl₂ to give the title product and a small amount of theBOC-protected di-iodo compound. Trituration of the mixture withether/hexane removes the undesired compound leaving the title product inthe solution. Filtration of the solid and concentration of the filtrateyields the title product (18.95 g, 59.2 mmol).

[1160]¹H NMR (CDCl₃, 300 MHz) δ8.75(s, 1H), 8.35(d, 1H), 8.1(d, 1H),7.0(bs, 1H), 1.55(s, 9H).

[1161] C. (2-Oxo-1-prop2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid benzylester

[1162] Sodium hydride (1.11 g, 27.7 mmol, 60% mineral oil dispersion) isadded to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid benzylester (6.20 g, 26.4 mmol) in THF/DMF (88 mL, 3/1 v/v) at 0° C. Themixture is stirred for 5 min. then propargyl bromide (4.4 mL, 49.4 mmol)is added dropwise. The resulting solution is stirred for 1 h thenbrought to room temperature and stirred for 2 h. The reaction isquenched with saturated ammonium chloride solution then diluted withethyl acetate and washed with water (×4) and brine. The organic layer isdried over MgSO₄, filtered and concentrated to dryness. The residue ispurified by column chromatography eluting with 5% MeOH/CH₂Cl₂ to givethe product (7.20 g, 26.4 mmol) as a white solid.

[1163]¹H NMR (CDCl₃, 300 MHz) δ7.35 (m, 5H), 5.30 (bs, 1H), 5.12(s, 2H),4.21(m,1H), 4.13 (s, 2H), 3.43(m, 2H), 2.73 (m, H), 2.25 (s, 1H), 1.95(m, 1H).

[1164] D.2-[3-(S)-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester

[1165] Pd(PPh₃)₂Cl₂ (0.49 g, 0.70 mmol), Cul (0.08 g, 0.42 mmol)followed by triethylamine (7.8 mL, 56.0 mmol) is added to a solution of(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid benzyl ester(3.81 g, 13.9 mmol) and (3-iodo-pyridin-4-yl)-carbamic acid tert-butylester (4.48 g, 14.0 mmol) in DMF (50 mL) at room temperature. Themixture is heated to 100° C. and stirred for 1.5 h. The reaction mixtureis then cooled to 50° C. and DBU (4.2 mL, 28.1 mmol) is added. After 30min the solution is cooled to room temperature, diluted with ethylacetate and washed with saturated ammonium chloride, water and brine.The organic layer is dried over MgSO₄, filtered and concentrated todryness in vacuo. The resulting solid is purified by columnchromatography eluting with a gradient of 2% MeOH/CH₂Cl₂ to 5%MeOH/CH₂Cl₂ to give the product (4.79 g, 10.3 mmol) as a white solid.

[1166]¹H NMR (CDCl₃, 300 MHz) δ8.80 (s, 1H), 8.48 (d, 1H), 7.90 (d, 1H),6.51 (s, 1H), 7.39 (m, 5H), 5.45 (d, 1H), 5.19 (s, 2H), 4.90 (AB, 2H),4.30 (m, 1H), 3.49 (m, 2H), 2.75 (m, 1H), 2.10 (m, 1H), 1.78 (s, 9H).Ion spray MS, [M+H]⁺=465.

[1167] E.2-[3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester

[1168]2-[3-(S)-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester (2.8 g, 6.0 mmol) in HCO₂H/MeOH (30 mL, 4.4%solution) is quickly added via cannula to a solution of palladium black(2.0 g, 18.8 mmol) in water (1 mL). After ca. 40 min the catalyst isfiltered through Celite and basified with saturated sodium bicarbonatesolution. The filtrate is concentrated in vacuo to remove methanol thenthe resulting solution is extracted with methylene chloride. The organiclayer is washed with brine, dried over MgSO₄, filtered and concentratedto dryness. The resulting white solid can be used in the subsequent stepwithout further purification. The title compound was purified in thefollowing manner to prepare a focused sulfonamide library. The crudesolid was purified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O(0.1% TFA) to 100% CH₃CN. The appropriate fractions are combined andneutralized with saturated sodium bicarbonate solution then concentratedto remove CH₃CN. The aqueous layer is extracted with methylene chloride(×4) and the organic layers are washed with brine, dried over MgSO₄,filtered and concentrated to give the title compound as a white solid.

[1169]¹H NMR (CDCl₃, 300 MHz) δ8.80 (s, 1H), 8.43 (d, 1H), 7.90 (d, 1H),6.41 (s, 1H), 4.88 (AB, 2H), 3.65 (m, 1H), 3.45 (m, 2H), 2.55 (m, 1H),1.90 (m, 1H), 1.75 (s, 9H). Ion spray MS, [M+H]⁺=331.

[1170] F. 5-Chloro-[2,2′]bithiophenyl

[1171] The title compound is prepared from 2-chloro-thiophene accordingto the procedure described in Bull Chem. Soc. Japan, 1979, 1126. Thecrude product is purified by column chromatography eluting with agradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to afford a whitesolid.

[1172]¹H NMR (CDCl₃, 300 MHz) δ7.24 (m, 1H), 7.11 (d, 1H), 7.03 (dd,1H), 6.94 (d, 1H), 6.83 (d, 1H). EI MS, [M]⁺=200, 202, Cl pattern.

[1173] G. 5′-Chloro-[2,2′]bithiophenyl-5-sulfonyl chloride

[1174] The title compound is prepared as described in EXAMPLE 57, Part Ausing 5-chloro[2,2′]bithiophenyl in place of thieno[2,3-b]pyridine. Thecrude product is purified by column chromatography eluting with agradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to give a white solid.

[1175]¹H NMR (CDCl₃, 300 MHz) δ7.76 (d, 1H), 7.14 (d, 1H), 7.09 (d, 1H),6.92 (d, 1H). EI MS, [M]⁺=298, 300, Cl pattern.

[1176] H.2-[3-(S)-(5′-Chloro-[2,2′]bithiophenyl-5-sulfonylamino)2-oxo-pyrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester

[1177] The title compound is prepared as described in EXAMPLE 56, Part Ausing 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and2-[3-(S)amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester as starting material. The crude product can bepurified by column chromatography eluting with 5% MeOH/CH₂Cl₂ to givethe title compound as a white solid or used in the subsequent step afteran aqueous work-up without further purification. Ion spray MS,[M+H]⁺=593, 595, Cl pattern.

[1178] 1. 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide

[1179] Trifluoroacetic acid (1.0 mL, 13.0 mmol) is added dropwise to aslurry of2-[3-(S)-(5′-chloro-[2,2′]bithiophenyl-5-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester (0.13 g, 0.22 mmol) in CH₂Cl₂ (2 mL) at 0° C.After 30 min, the ice bath is removed and the solution is stirred atroom temperature for 4 h. The reaction mixture is concentrated todryness and the crude product is purified by RP-HPLC eluting in agradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. The appropriateproduct fractions are lyophilized to provide the title compound as awhite solid.

[1180]¹H NMR (DMSO-d₆, 300 MHz) δ14.60 (bs, 1H), 12.78 (s, 1H), 9.18 (s,1H), 8.55 (d, 1H), 8.40 (d, 1H), 7.88 (d, 1H), 7.61 (d, 1H), 7.38 (d,1H), 7.36 (d, 1H), 7.21 (d, 1H), 6.91 (s, 1H), 4.70 (AB, 2H), 4.21 (m,1H), 3.30 (m, 2H), 2.25 (m, 1H), 1.75 (m, 1H). Ion spray MS, [M+H]⁺=493,495, Cl pattern.

EXAMPLE 60

[1181] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[1182] A. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl ester

[1183] n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol)is added dropwise to a solution of ethyldiethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared asdescribed in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL).The mixture is stirred for 20 min. then5-chloro-2-thiophenecarboxaldehyde (0.45 mL, 4.2 mmol) is slowly added.The yellow mixture is stirred at −78° C. for 1 h then allowed to warm toroom temperature overnight. The bulk of the solvents are evaporated andthe residue is treated with water (2 mL) and extracted with CH₂Cl₂. Theorganic layer is washed with brine, dried over MgSO₄, filtered andconcentrated. The crude product is purified by column chromatographyeluting with CH₂Cl₂to give the title compound as a yellow solid.

[1184]¹H NMR (CDCl₃, 300 MHz) δ7.55 (d, 1H), 7.11 (d, 1H), 6.90 (d, 1H),6.41 (d, 1H), 4.20 (q, 2H), 1.39 (t, 3H). Ion spray MS, [M+H]⁺=253.

[1185] B. 2-(5-Chloro-thiophen-2-yl)-ethene tetra-n-butylammoniumsulfonate

[1186] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl ester (0.92g, 3.2 mmol) in acetone (16 mL) is treated with tetrabutylammoniumiodide (1.3 g, 3.5 mmol) and heated to reflux for 19 h. The mixture isconcentrated to dryness then diluted with CH₂Cl₂ and washed with waterand brine. The organic layer is dried over MgSO₄, filtered andconcentrated to give an oil/solid which is taken on to the next stepwithout further purification.

[1187]¹H NMR (CDCl₃, 300 MHz) δ7.28 (d, 1H), 6.81 (d, 1H), 6.77 (d, 1H),6.73 (d, 1H), 3.29 (t, 8H), 1.65 (m, 8), 1.45 (m, 8H), 1.00 (t, 12H).

[1188] C. 2-(5-Chlorothiophen-2-yl)-ethenesulfonyl chloride

[1189] Sulfuryl chloride (0.61 mL, 7.6 mmol) is added to a solution oftriphenylphosphine (1.8 g, 6.9 mmol) in CH₂Cl₂ (8.6 mL) at 0° C. The icebath is removed and 2-(5-chloro-thiophen-2-yl)-ethenetetra-n-butylammonium sulfonate (1.6 g, 3.4 mmol) in CH₂Cl₂(17 mL) isadded to the reaction mixture via cannula. The resulting yellow solutionis stirred for 1.5 h then hexane/ether (1:1 v/v, 200 mL) is added untilthe solution is no longer cloudy and two layers form. The solution isdecanted and the lower oily layer is discarded. The solution isconcentrated to dryness and the product is purified by columnchromatography eluting with CH₂Cl₂to give the title compound as a paleyellow solid.

[1190]¹H NMR (CDCl₃, 300 MHz) δ7.71 (d, 1H), 7.25 (d, 1H), 7.00 (d, 1H),6.91 (d, 1H). EI MS, [M.]⁺=242, 244, 246, Cl pattern.

[1191] D.2-{3-(S)-[2-(5-Chloro-thiophene-2-yl)-ethenesulfonylamino]2-oxo-pyrrolidin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester

[1192] The title compound is prepared as described in EXAMPLE 56, Part Ausing 2-(5-chlorothiophen-2-yl)-ethenesulfonyl chloride and2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester as starting material. The crude product can bepurified by column chromatography eluting with 5% MeOH/CH₂Cl₂to give thetitle compound as a white solid or used in the subsequent step after anaqueous work-up without further purification.

[1193]¹H NMR (CDCl₃, 300 MHz) δ8.75 (s, 1H), 8.46 (d, 1H), 7.85 (d, 1H),7.48 (d, 1H), 7.05 (d, 1H), 6.85 (d, 1H), 6.67 (d, 1H), 6.40 (s, 1H),4.90 (AB, 2H), 4.15 (m, 1H), 3.49 (m, 2H), 2.71 (m, 1H), 2.21 (m, 1H),1.7 (s, 9H). Ion spray MS, [M+H]⁺=537, 539, Cl pattern.

[1194] E. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[1195] The title compound is prepared as described in EXAMPLE 59, Part Iusing2-{3-(S)-[2-(5-chloro-thiophene-2-yl)-ethenesulfonylamino]-2-oxo-pyrrolidin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester as starting material. The crude product ispurified by RP-HPLC eluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA)to 100% CH₃CN. The appropriate fractions are lyophilized to provide thetitle compound as a white solid.

[1196]¹H NMR (DMSO-d₆, 300 MHz) δ9.19 (s, 1H), 8.48 (d, 1H), 7.91 (d,1H), 7.88 (d, 1H), 7.50 (d, 1H), 7.43 (d, 1H), 7.20 (d, 1H), 7.02 (d,1H), 6.90 (s, 1H), 4.71 (AB, 2H), 4.12 (m, 1H), 3.21 (m, 2H), 2.42 (m,1H), 1.85 (m, 1H). EI MS, [M.]⁺=436, 438, Cl pattern.

EXAMPLE 61

[1197] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1198] A. 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1199] The title compound is prepared as described in EXAMPLE 56, Part Ausing 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material. The crude product is purified bycolumn chromatography eluting with 5% MeOH/CH₂Cl₂ to give the titlecompound as a white solid.

[1200]¹H NMR (CDCl₃, 300 MHz) δ8.30 (d, 1H), 8.15 (s, l1H), 7.82 (d,1H), 7.52-7.60 (m, 3H), 7.01-7.09 (m, 2H), 6.88 (d, 1H), 5.41 (s, 1H),4.68 (AB, 2H), 3.90 (m, 1H), 3.29 (m, 2H), 2.61 (m, 1H), 2.11 (m, 1H).Ion spray MS, [M+H]⁺=538, 540, Cl pattern.

[1201] B. 5′-Chloro-[2,2′[bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1202] The title compound is prepared as described in EXAMPLE 56, Part Busing 5′-chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amideas starting material. The crude product is purified by RP-HPLC elutingwith a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. Theappropriate fractions are lyophilized to provide the title compound as awhite solid.

[1203]¹H NMR (DMSO-d₆, 300 MHz) δ9.03 (bs, 2H), 8.58 (d, 1H), 8.31 (s,1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.30-7.41(m, 2H), 7.29-7.25 (m, 2H), 4.60 (AB, 2H), 4.25 (m, 1H), 3.23 (m, 2H),2.20 (m, 1H), 1.75 (m, 1H). Ion spray MS, [M+H]⁺=519, 521, Cl pattern.

EXAMPLE 62

[1204] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl1)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1205] The title compound is prepared as described in EXAMPLE 56, Part Busing 2-(5-chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amideas starting material. The crude product product is purified by RP-HPLCeluting with a gradient of 10% CH₃CN/H₂O (0.1% TFA) to 100% CH₃CN. Theappropriate fractions are lyophilized to provide the title compound as apale pink solid.

[1206]¹H NMR (DMSO-d₆, 300 MHz) δ9.00 (bs, 2H), 8.32 (s, 1H), 7.90-7.98(m, 2H), 7.80 (d, 1H), 7.63 (d, 1H), 7.50 (d, 1H), 7.48 (d, 1H), 7.25(d, 1H), 7.18 (d, 1H), 7.00 (d, 1H), 6.73 (d, 1H), 4.52 (AB, 2H), 4.20(m, 1H), 3.23 (m, 2H), 2.48 (m, 1H), 1.88 (m, 1H). Ion spray MS,[M+H]⁺=463, 465, Cl pattern.

EXAMPLE 63

[1207] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-6yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1208] The title compound is prepared as described in example 28 PartsE, F, G using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride

[1209]¹H NMR (DMSO-d₆, 300 MHz) δ9.83 (bs, 2H), 8.86 (m, 2H), 8.25 (s,1H), 8.11 (s, 1H), 8.00 (m, 3H), 7.85 (m, 2H), 7.55 (m, 1H), 4.50 (AB,2H), 4.15 (m, 1H), 3.14 (m, 2H), 2.17 (m, 1H), 1.72 (m, 1H). FAB MS,[M+H]⁺488, 490; Cl pattern.

EXAMPLE 64

[1210] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1211] The title compound is prepared as described in example 29 PartsF, G and H using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride.

[1212]¹H NMR (DMSO-d₆, 300 MHz) δ8.78 (m, 2H), 8.28 (m, 2H), 8.04 (m,2H), 7.82 (m, 2H), 7.51 (d, 1H), 7.40 (s, 1H), 4.58 (AB, 2H), 4.13 (m,1H), 3.19 (m, 2H), 2.17 (m, 1H), 1.68 (m, 1H). FAB MS, [M+H]⁺=494, 496;Cl pattern.

EXAMPLE 65

[1213] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1214] The title compound is prepared as described in example 30 PartsD, E using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride

[1215]¹H NMR (DMSO-d₆, 300 MHz) δ8.52 (m, 2H), 8.20 (m, 1H), 8.11 (s,1H), 7.91 (m, 2H), 7.71 (s, 1H), 7.42 (m, 1H), 7.30 (m, 2H), 4.58 (AB,2H), 4.15 (m, 1H), 3.21 (m, 2H), 2.20 (m, 1H), 1.72 (m, 1H). FAB MS,[M+H]⁺=494, 496; Cl pattern.

EXAMPLE 66

[1216] 5′-Chloro-[2,2′]bithiophenyl-5-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1217] The title compound is prepared as described in example 30 PartsD, E using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride.

[1218]¹H NMR (DMSO-d₆, 300 MHz) δ9.30 (m, 2H), 8.70 (m, 1H), 8.44 (m,1H), 8.20 (m, 1H), 7.55 (m, 1H), 7.21 (m, 2H), 7.00 (m, 1H), 4.57 (AB,2H), 4.15 (m, 1H), 3.20 (m, 2H), 2.19 (m, 1H), 1.70 (m, 1H). FAB MS,[M+H]⁺=526, 528; Cl pattern.

EXAMPLE 67

[1219]2-(3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid tert-butyl ester.

[1220] A. (2-Bromo-pyridin-3-yl)-carbamic acid tert-butyl ester

[1221] To a solution of 3-amino-2-bromopyridine (1.5 g, 8.7 mmol) anddi-tert-butyl dicarbonate (2.0 g, 9.2 mmol) in THF (15 ml) is added 1.0M sodium bis(trimethylsilyl)amide in THF (18 ml, 18 mmol) at 0° C. Themixture is stirred at r.t. for 4 h, and then concentrated, quenched withsaturated NH₄Cl, diluted with EtOAc, and washed with water. The organiclayer is dried over MgSO₄, treated with charcoal, filtered andconcentrated to dryness. Title compound is obtained as a light yellowsolid (2.1g, 7.7 mmol).

[1222]¹H NMR (CDCl₃, 300 MHz) δ8.44 (d, 1H), 8.03 (d, 1H), 7.20 (m,111), 7.02 (bs, 1H), 1.50 (s, 9H). EI MS [M+H]⁺=273, 275.

[1223] B.2-(3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid tert-butyl ester

[1224] The title compound is prepared from(2-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.6 g, 5.9 mmol)and (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl carbamic acid benzyl ester(1.6 g, 5.9 mmol) according to the methods described in EXAMPLE 59,Parts C,D and E. The title compound was obtained as a white solid (0.29g, 0.88 mmol).

[1225]¹H NMR (CDCl₃, 300 MHz) δ8.45 (d, 1H), 8.27 (d, 1H), 7.18 (dd,1H), 6.50 (s, 1H), 4.90 (AB, 2H), 3.64 (m, 1H), 3.45 (m, 2H), 2.52 (m,1H), 1.85 (m, 1H), 1.70 (s, 9H). EI MS [M+H]⁺=331.

EXAMPLE 68

[1226] 6-Chloro-1H-benzimidazole-2-sulfonyl chloride

[1227] A mixture of 4-chloro-1,2-phenylenediamine (4.3 g, 30 mmol),potassium hydroxide (1.9 g, 34 mmol), carbon disulfide (2.1 ml, 34mmol), ethanol (30 ml) and water (4.5 ml) is heated under reflux for 3h. Norit is added, the mixture is refluxed 10 min, then filtered. Thewarm filtrate is diluted with water (30 ml, 50-75° C.) followed byaqueous acetic acid (7.5 ml, 33%) with stirring. Brown solid forms, andthe mixture is cooled with an ice bath.6-Chloro-1H-benzimidazole-2-thiol (4.2 g, 2.3 mmol) is collected, washedwith water and vacuum dried.:

[1228]¹H NMR (DMSO-d₆, 300 MHz) δ12.6 (d, 2H), 7.1 (s, 3H). EI MSM⁺=184, 186. A suspension of 6-chloro-1H-benzimidazole-2-thiol (1.0 g,5.4 mmol) in 20% AcOH (30 ml) is cooled in an ice bath; Cl₂ gas isbubbled through the mixture for 40 min. The resulting solid is collectedby filtration, washed with H₂O and air dried to give the title compoundas a light brown solid.

[1229]¹H NMR (CDCl₃, 300 MHz) δ7.75 (m, 2H), 7.50 (d, 1H).

EXAMPLE 69

[1230] Thieno[2,3-b]pyridine-2-sulfonyl chloride

[1231] Thieno[2,3-b]pyridine (1.18 g, 8.7 mmol) is to subjected to thethree step sequence described in EXAMPLE 8, Part A. Flash chromatography(20% EtOAc/Hexane) of the crude product gives the title compound (0.59g, 2.5 mmol):

[1232]¹H NMR (CDCl₃, 300 MHz) δ8.78 (dd, 1H), 8.26 (dd, 1H), 8.10 (s,1H), 7.47 (dd, 1H). EI MS M⁺=233, 235.

EXAMPLE 70

[1233] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl chloride

[1234] 6-Chloro-thieno[2,3-b]pyridine (0.73 g, 4.3 mmol) is to subjectedto the three step sequence sequence described in EXAMPLE 8, Part A.Flash chromatography (15% EtOAc/Hexane) of the crude product gives thetitle compound (0.75 g, 2.8 mmol):

[1235]¹H NMR (CDCl₃, 300 MHz) δ8.19 (d, 1H), 8.07 (s, 1H), 7.47 (d, 1H).EI MS M⁺=267, 269, 271.

[1236] The compounds of Examples 71-74 are synthesized using methods andreagents analogous to those described herein.

EXAMPLE 71

[1237] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1238] EI MS, [M]⁺469.

EXAMPLE 72

[1239] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1240] ESI MS, [M+H]⁺=463, 465 (Cl pattern).

EXAMPLE 73

[1241] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1242] EI MS, [M+H]⁺=519, 521 (Cl pattern).

EXAMPLE 74

[1243] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide

[1244] EI MS, [M+H]⁺=436, 438 (Cl pattern).

EXAMPLE 75

[1245] 3-(R)-5 Chlorothiophen-2-yl)ethenesulphonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1246] Part A 7-Methyloxycarbonyl-4-chloro-quinoline

[1247] 4-Chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mmol) in 100 mL80% H₂SO₄ is heated to 200° C. for 24 hours in a sealed tube. Thesolution is cooled, poured into water and neutralized with sodiumhydroxide to pH ˜3-4. The precipitated solid is collected, washed withwater and dissolved in 2 N sodium hydroxide. The aqueous solution iswashed with ethyl acetate then acidified to pH˜3-4. The precipitate iscollected, washed with water and dried in a vacuum oven overnight toyield 7-carboxy-4-chloroquinoline as a solid (5.1 g, 24.6 mmol). Aportion of this material (2.0 g, 9.6 mmol) is treated with anhydrous THF(200 mL) and DMF (2 mL) and 2 M oxalyl chloride in methylene chloride(14.5 mL, 29 mmol). The resulting suspension is stirred at roomtemperature for 2 h then treated with methanol (10 mL). After stirring30 min. the solution is concentrated and the residue is taken up inmethylene chloride. The solution is washed with saturated sodiumbicarbonate and dried (sodium sulfate) and concentrated to yield thetitle compound as a solid (2.1 g, 9.5 mmol). MS m/z: M⁺=221;

[1248]¹H NMR (CDCl₃, 300 MHz) δ8.6 (s, 1H), 8.2 (s, 1H), 7.9 (d, 1H),7.65 (d, 1H), 7.45 (s, 1H), 3.95 (s, 3H).

[1249] Part B 7-Hydroxymethyl-4-chloroquinoline

[1250] 7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) isdissolved in anhydrous THF (25 mL) and anhydrous ether (200 mL). Thesolution is cooled in a dry ice/acetone bath and treated 1 M lithiumaluminum hydride in THF (11.0 mL, 11 mmol). The solution is warmed(approximately −45° C.) for 20 min. and quenched with ethyl acetate. Thesolution is diluted with ether (100 mL) and treated with water (36 mL),15% NaOH (36 mL) and water (3×36 mL) in succession. The mixture isfiltered and evaporated to yield the title compound as a residue (2.0 g,9.7 mmol) which is dried under vacuum and used without furtherpurification. MS m/z: M⁺=193;

[1251]¹H NMR (CDCl₃, 300 MHz) δ0.00, 8.65 (d, 1H), 8.15 (d, 1H), 8.0 (d,1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s, 2H).

[1252] Part C 7-Bromomethyl-4-chloroquinoline

[1253] 7-Hydroxymethyl4-chloroquinoline (0.2 g, 0.97 mmol) is treatedwith 48% HBr and heated to 120° C. for 1 h. The resulting solution iscooled with ice, diluted with water and treated with ethyl acetate andsodium bicarbonate until basic to pH paper. The layers are separated andthe organic layer is washed with water, dried (Na₂SO₄) and concentratedto give 7-Bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z:M⁺=255;

[1254]¹H NMR (CDCl₃, 300 MHz) δ8.75 (d, 1H), 8.25 (d, 1H), 8.1 (s, 1H),7.7 (d, 1H), 7.5 (d, I1), 4.7 (s. 2H).

[1255] Part D3-amino-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidinoneHydrochloride

[1256] 3-(R)-(t-butylcarbamyl)2-oxo-pyrrolidinone (1.0 g, 5.0 mmol) isdissolved in THF (70 mL), cooled in an ice bath and treated withtretrabutylammonium iodide (0.18 g) and 60% sodium hydride (0.24 g, 6.0mmol). The reaction mixture is stirred at 0° C. for 30 min. then treateddropwise with a solution of 7-bromomethyl-4-chloroquinoline (1.3 g, 5.1mmol) in THF (50 mL). The resulting solution is stirred at 0° C. for 2 hthen quenched with ammonium chloride solution and concentrated. Dilutionwith ethyl acetate is followed by a water wash; the organic layer isdried (sodium sulfate) and concentrated. The residue is chromatographed(3% methanol/methylene chloride) to yield solid3-(R)-(t-butylcarbamyl)-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidinone(1.3 g, 3.3 mmol). This material is treated with a saturated solution ofHydrogen chloride in ethyl acetate is stirred for 2 h at room temp. Thesolid is filtered, washed with ethyl ether and air dried to give thetitle compound (0.95 g, 3.0 mmol) MS m/z: M⁺=;

[1257]¹H NMR (CD₃OD, 300 MHz) 9.0 (d, 1H), 8.5 (d, 1H), 8.15 (s, 1H),8.0 (d, 1H), 7.9 (d, 1H), 4.9 (q, 2H), 4.2 (t, 1H) 3.4 (m, 2H), 2.65 (m,1H), 2,1 (m, 1H)

[1258] Part E 3-(R)-5 Chloro-thiophen-2-yl)-ethenesulphonicacid[1-(4-Chloroquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide

[1259] 3-amino-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidinoneHydrochloride (40,0 mg, 0.12 mol) is treated with DMF (2 ml),acetonitrile (8 mL), triethyl amine (1.2 ml, 8.4 mmol) and a solution of5-Chloro-thiophen-2-yl)-ethenesulphonyl chloride (30.0 mg, 0.12 mmol) inacetonitrile (2.0 mL) at 0° C. After 2 h the solution is poured intowater and extracted with ethyl acetate. The organic layer is washed withwater, dried over sodium sulfate and concentrated to yielded the titlecompound (28 mg, 0.5 mmol). MS m/z: 481 [M+1]⁺;

[1260]¹H NMR (CDCl3, 300 MHz) δ8.8 (d, 1H), 8.15 (d, 1H), 7.9 (d, 2H),7.85 (s, 1H), 7.4-7.5 (m, 2H) 6.7 (d, 1H), 6.6 (d, 1H), 6.5 (d, 1H),5.8-5.9 (m, 1H), 4.75 (q, 2H), 4.2 (t, 11H), 3.3-3.4 (m, 2H), 2.6 (m,1H), 2.0 (m, 1H).

[1261] Part F 3-(R)-5-Chloro-thiophen-2-yl)ethenesulphonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1262] 3-(R)-5 Chloro-thiophen-2-yl)-ethenesulphonicacid[1-(4-Chloro-quinolin-7-ylmethyl)2-oxo-pyrrolidin-3-yl]-amide (20mg), ammonium acetate (0.5 g), and phenol (1.0 g) are heated in a sealedtube at 120° C. for 1.5 hours. The vessel contents are diluted withethyl acetate and washed with 1 N NaOH (4×100 ml), water, concentrated,and purified by HPLC (20% acetonitrile in 0.1% aqueous TFA to 100%acetonitrile) and lyophylized to give 2.0 mg of the title compound: MSm/z: 463 [M+H]

[1263]¹H NMR (CD3OD, 300 MHz) 8.3 (m, 1H), 7.7 (s, 1H), 7,6 (d, 1H), 7.5(d, 1H), 7.2 (d, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6,8 ( d, 1H), 4.9 (q,2H), 4.25 (t, 1H), 3,5 (m, 2H), 2.6 (m, 1H), 2.05 (m, 1H).

[1264] The compounds of Examples 76-81 are synthesized using methods andreagents analogous to those described herein.

EXAMPLE 76

[1265]3-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-chloro-benzo[b]thiophene-2-sulfonyl)-amino]-aceticacid methyl ester, trifluoroacetate

[1266] ESI MS, [M+H]⁺=559, 561.

EXAMPLE 77

[1267] 3-(S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate

[1268] ESI MS, [M+H]⁺=487, 489.

EXAMPLE 78

[1269] 3-(S)-5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate

[1270] ESI MS, [M+H]⁺=463, 465.

EXAMPLE 79

[1271] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-quinolin-6-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide,ditrifluoroacetate

[1272] ESI MS, [M+H]⁺=454.

EXAMPLE 80

[1273]N-(3-Amino-pyridin-4-yl)2-[3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-acetamide

[1274] MS, [M+H]⁺=470.

EXAMPLE 81

[1275]2-[3-(7-Methoxy-naphthalene-2-sulfonylamino-2-oxo-pyrrolidin-1-yl]-N-pyridin-4-yl-acetamide

[1276] MS, [M+H]⁺=455.

EXAMPLE 82

[1277] 6-Chloro-benzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)yl}-amidetrifluoroacetate

[1278] Part A [1-(2-Amino-ethyl)-2-oxo-pyrrolidin-3(S)- yl]-carbamicacid tert-butyl ester [2-Oxo-pyrrolidin-3(S)-yl]-carbamic acidtert-butyl ester (4.0 g, 20 mmol) is dissolved in THF (150 mL), cooledin an ice bath and treated with 60% sodium hydride (0.95 g, 24 mmol).The reaction mixture is stirred for 30 min., then treated withtetra-butylammonium iodide (0.16 g, 0.44 mmol) and bromoacetonitrile(1.7 mL, 24 mmol). After 3 h the reaction is quenched with water,concentrated to a small volume and extracted with methylene chloride(4×). The combined organic extracts are concentrated and the residue ischromatographed (2% MeOH/CH₂Cl₂) to give[1-cyanomethyl-2-oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester(3.4 g, 14 mmol). ). EI MS m/z: 240, [M+1]⁺;

[1279]¹H NMR (CDCl₃, 300 MHz) δ5.08 (br, 1H), 4.27 (m, 2H), 4.15 (m,1H), 3.47 (m, 2H), 2.68 (m, 1H), 2.00 (m, 1H), 1.45 (s, 9H). Thismaterial (3.0 g, 12.6 mmol) is dissolved in ethanol (80 mL) and treatedwith platinum oxide (0.8 g) at 50 PSI of hydrogen gas for 24 h. Thecatalyst is removed by filtration and the solution is concentrated toyield the title compound (2.9 g, 12 mmol). EI MS m/z: 244, [M+1]⁺;

[1280]¹H NMR (CDCl₃, 300 MHz) δ5.13 (br, 1H), 4.13 (m, 1H), 3.34 (m,5H), 2.85 (t, 1H), 2.60 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H).

[1281] Part B{2-Oxo-1-[2-(2,3,5,6-tetrachloro-pyridin-4-ylamino)-ethyl]-pyrrolidin-3(S)-yl}-carbamicacid tert-butyl ester

[1282] [1-(2-Amino-ethyl)-2-oxo-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (2.7 g, 11 mmol) is dissolved in methylene chloride(100 mL) and treated with 4-nitro-2,3,5,6-tetrachloro-pyridine (3.2 g,12 mmol) and N-methylmorpholine (2.6 mL, 24 mmol). The reaction mixtureis stirred for 5 h, concentrated and the residue is purified bychromatography (50-60% ethyl acetate/hexane) to give the title compound(3.2 g, 7.0 mmol). EI MS m/z: 456, 458, 460, 462 [M]⁺;

[1283]¹H NMR (CDCl₃, 300 MHz) δ5.6 (br, 1H), 5.07 (br, 1H), 4.15 (m,1H), 3.94 (m, 2H), 3.60 (m, 2H), 3.36 (m, 2H), 2.65 (m, 1H), 1.98 (m,1H), 1.44 (s, 9H).

[1284] Part C3-(S)-Amino-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-2-one{2-Oxo-1-[2-(2,3,5,6-tetrachloro-pyridin-4-ylamino)-ethyl]-pyrrolidin-3(S)-yl}-carbamicacid tert-butyl ester (0.42 g, 0.92 mmol) is dissolved in methanol (16mL) and treated with 0.5 M sodium methoxide in methanol (18 mL, 8 mmol).The solution is treated with 10% Pd/C and agitated under 60 PSI ofhydrogen gas for 16 h. The solvent is removed and the residue is treatedwith saturated NH₄Cl and then saturated NaHCO₃. The aqueous solution isextracted with methylene chloride (8×). The methylene chloride layer isdried (MgSO₄) and concentrated to a white foam (0.19 g, 5.9 mmol). EI MSm/z: 321, [M+1]⁺;

[1285]¹H NMR (CDCl₃, 300 MHz) δ8.20 (d, 2H), 6.45 (d, 2H), 5.1 (br, 1H),4.9 (br, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3,4 (m, SH), 2.57 (m, 1H), 1.96(m, 1H), 1.46 (s, 9H). This material (0.14 g, 0A4 mmol) is treated with20% trifluoroacetic acid in methylene chloride (10 mL) at ambienttemperature for 2 h. Concentration of the solution gives clean productin the form of TFA salt. The free base (0.072 g, 0.33 mmol) is obtainedby applying the TFA salt to a silica gel column and eluting withNH₄OH/MeOH/CH₂Cl₂ (1:10:70). APCI MS m/z: 221, [M+1]⁺;

[1286]¹H NMR (CDCl₃, 300 MHz) δ8.17 (d, 2H), 6.40 (d, 2H), 4.90 (br,1H), 3.55 (m, 3H), 3,34 (m, 4H), 2.42 (m, 1H), 1.80 (m, 1H).

[1287] Part D 6-Chloro-benzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-yl-amino)-ethyl]-pyrrolidin-3(S)-yl}-amidetrifluoroacetate

[1288] 3-(S)-Amino-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-2-one(0.12 mmol) is dissolved in MeCN (5 mL) and treated with4-methylmorphorline (0.035 mL, 0.32 mmol);6-chlorobenzo[b]thio-phene-2-sulfonyl chloride (0.033 g, 0.12 mmol) inMeCN (1 mL) is added dropwise. The reaction mixture is stirred at r.t.for 2 h, then subjected to HPLC purification, to give the title compoundas white solid (0.060 g, 0.11 mmol). MS m/z 451, 453 [M+1]⁺;

[1289]¹H NMR (CD₃OD, 300 MHz) δ8.15 (d, 1H), 8.05 (s, 1H), 8.0 (m, 2H),7.03 (d, 1H), 6.96 (dd, 1H), 6.82 (dd, 1H), 4.05 (t, 1H), 3.60-3.35 (m,6H), 2.37 (m, 1H), 1.83 (m, 1H).

[1290] The compounds of Examples 83-88 are synthesized using methods andreagents analogous to those described herein.

EXAMPLE 83

[1291] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-etlyl]-pyrrolidin-3-yl}-amide

[1292] MS, [M+H]⁺=483, 485.

EXAMPLE 84

[1293] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoacetate

[1294] MS, [M+H]⁺=452, 454.

EXAMPLE 85

[1295] Thieno[3,2-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amideditrifluoroacetate

[1296] MS, [M+H]⁺=418.

EXAMPLE 86

[1297] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl }-amide

[1298] MS, [M+H]⁺=427, 429.

EXAMPLE 87

[1299] (S)-5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate

[1300] MS, [M+H]⁺=532, 534, 536.

EXAMPLE 88

[1301] (S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate

[1302] MS, [M+H]⁺=500, 502, 504.

EXAMPLE 89

[1303]((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester

[1304] To a DMF (2 ml) solution of 6-chloro-benzo[b]thiophene-2-sulfonicacid is added{2-oxo-1-[2-(pyridin4-yl-amino)-ethyl]-pyrrolidin-(S)-yl}-amide (0,030 g0.066 mmol) and K₂CO₃ (0.027 g, 0.2 mmol). After stirring at r.t. for 10min., methyl bromoacetate ( 0.01 ml, 0.1 mmol) is added and the mixtureis stirred for 3 h. The solvent is removed, and the residue is purifiedby chromatography using NH₄OH/MeOH/CH₂Cl₂ (1:5:95) as eluant. The titlecompound is obtained as a white solid (0.011 g, 0.021 mmol). MS m/z 523,525 [M+1]⁺;

[1305]¹H NMR (CDCl₃, 300 MHz) δ8.15 (d, 2H), 7.98 (s, 1H), 7.84 (s, 1H),7.80 (d, 1H), 7.41 (d, 1H), 6.35 (d, 2H), 4.72 (br, 1H), 4.55 (t, 1H),4.18 (d, 1H), 3.85 (d, 1H), 3.70 (s, 3H), 2.55 (m, 1H), 3.4 (m, 5H),2.60 (m, 1H), 2.35 (m, 1H).

[1306] The compounds of Examples 90-100 are synthesized using methodsand reagents analogous to those described herein.

EXAMPLE 90

[1307]((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate

[1308] MS. [M+H]⁺=509, 511.

EXAMPLE 91

[1309] 6-Chloro-benzo[b]thiophene-2-sulfonic acidallyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide

[1310] MS, [M+H]⁺491, 493.

EXAMPLE 92

[1311] 6-Chloro-benzo[b]thiophene-2-sulfonic acidmethyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide

[1312] MS, [M+H]⁺=465, 467.

EXAMPLE 93

[1313] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amidetrifluoroacetate

[1314] MS, [M+H]⁺=476, 478, 480.

EXAMPLE 94

[1315] (S)-Thieno[3,2-b]pyridine-2-sulfonicacid{-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate

[1316] MS, [M+H]⁺=467, 469.

EXAMPLE 95

[1317]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid methyl ester

[1318] MS, [M+H]⁺=499, 501.

EXAMPLE 96

[1319]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid isopropyl ester

[1320] MS, [M+H]⁺=527, 529.

EXAMPLE 97

[1321]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate

[1322] MS, [M+H]⁺=485, 487.

EXAMPLE 98

[1323] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoroacetate

[1324] MS, [M+H]⁺=485, 487.

EXAMPLE 99

[1325]([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid ethyl ester trifluoroacetate

[1326] MS, [M+H]⁺=513, 515.

EXAMPLE 100

[1327]3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-acrylamidetrifluoroacetate

[1328] MS, [M+H]⁺=390, 392.

EXAMPLE 101

[1329]1-1-(4Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chlorophenyl)ureatrifluoroacetate

[1330] A. (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester

[1331] N-a-(S)-tert-Butoxycarbonyl-α, γ-diaminobutyric acid (20 g, 92mmol) is suspended/dissolved in THF (360 mL), and 1-hydroxybenzotriazolehydrate (1 5.5 g, 100 mmol) added, followed by the addition oftriethylamine (28 g, 280 mmol). The suspension is stirred at roomtemperature for 15 minutes under nitrogen, before adding1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (22 g, 115mmol). The reaction mixture is heated at 60° C. for 22 hours, cooled,and the solids filtered off through a plug of silica. The solids andsilica are washed with THF until no more product is observed in thefiltrate by TLC. The combined filtrate is concentrated, and the residualyellow tacky solid is left under high vacuum overnight. The residualmaterial is triturated with ethyl acetate (100 mL), filtered off andwashed with ethyl acetate and ethyl ether, then dried under high vacuum.The product is isolated as fine colorless needles (12.2 g, 61 mmol).

[1332]¹H-NMR (CDCl₃, 300 MHz) δ6.18 (m, 1H); 5.11 (m, 1H); 4.15 (m, 1H);3.35 (m, 2H); 2.70 (m, 1H); 1.96 (m, 1H); 1.45 (s, 9H). ESI MS,[M+H]⁺=201.

[1333] B. 2-Benzylideneamino-4-methylbenzonitrile

[1334] Benzaldehyde(8.9 g, 84 mmol) is added to a suspension of2-amino-4-methylbenzonitrile (10.0 g, 76 mmol) in heptane (250 mL), andthe mixture refluxed under nitrogen overnight. The hot solution isdecanted into a pre-warmed flask to leave the insoluble brown oilmaterial behind, and the solution cooled to room temperature afteradding ethyl acetate (2mL). The resulting solid is filtered off andwashed with heptane:ethyl acetate=100:1 (2×25 mL), and dried under highvacuum to give a beige powder (12.54 g, 57 mmol).

[1335]¹H-NMR (CDCl₃, 300 MHz) δ8.46 (H, s); 7.95 (dd, 2H); 7.50 (m, 4H);7.07 (dd, 1H); 6.97 (s, 1H); 2.43 (s, 3H).

[1336] C. 2-Amino-4-(bromomethyl)benzonitrile

[1337] 2,2′-Azobisisobutyronitrile (AIBN) (1.31 g, 8 mmol) is added to asolution of N-bromosuccinimide (6.87 g, 38 mmol) and2-benzylideneamino-4-methylbenzonitrile (7 g, 31.8 mmol) in carbontetrachloride (250 mL), and the reaction mixture refluxed under nitrogenovernight. The reaction mixture is cooled and filtered through a plug ofcelite, and the celite washed with carbon tetrachloride (100 mL). Thecombined filtrate is washed with 1N HCl, saturated aqueous NaHCO₃, driedover MgSO₄ and concentrated in vacuo. The crude product is purified bycolumn chromatography on silica with 10-20% ethyl acetate/hexanes. Thecombined product fractions are concentrated, and the resulting stickysolid is washed with ethyl ether/hexanes to give the product as a paleyellow solid (3.26 g, 15 mmol).

[1338]¹H-NMR (CDCl₃, 300 MHz) δ7.36 (d, 1H); 6.75 (m, 2H); 4.45 (br s,2H); 4.35 (s, 2H). EI MS, [M+H]⁺=212.

[1339] D. [1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamicacid tert-butyl ester

[1340] (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1 g, 5mmol) is dissolved in THF (100 mL) under nitrogen, and cooled to 0° C.Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added in one portion tothe vigorously stirring solution, followed by 18-crown-6 (10 mg, 0.038mmol), and the reaction mixture allowed to warm to room temperature andstirred for 1 hour. The solution is cooled to 0° C. and2-amino-4-(bromomethyl)benzonitrile (1.16 g, 5.5 mmol) added dropwise asa solution in THF (10 mL), before leaving the reaction mixture to warmto room temperature and stir overnight. The reaction is quenched with0.25M HCl (20 mL), then neutralized with saturated aqueous NaHCO₃, andbrine added. The solution is extracted with ethyl acetate, and theorganic phase dried over MgSO₄, concentrated, and purified by columnchromatography on silica with 0.5-5% methanol/dichloromethane. Theproduct fractions are combined, concentrated, and the semi-solid oilyresidue triturated with hexanes/dichloromethane=100/1 (25 mL). Theproduct is isolated as a pale yellow powder (1.24 g, 3.75 mmol).

[1341]¹H-NMR (CDCl₃, 300 MHz) δ7.35 (d, 1H); 6.64 (d, 1H); 6.58 (dd,1H); 5.15 (br s, 1H); 4.40 (m, 4H); 4.19 (m, 1H); 3.24 (m, 2H); 2.60 (m,1H); 1.90 (m, 1H); 1.45 (s, 9H). ESI MS, [M+H]⁺331.

[1342] E.[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester

[1343] [1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650 mmo, 8mmol) are combined in ethanol (40 mL), and acetic acid (480 mg, 8 mmol)added. The reaction mixture is refluxed under nitrogen overnight, cooledand presorbed directly onto silica. The product is purified by columnchromatography on silica with 5-20% methanol/dichloromethane (containing0.5% of 28% aqueous ammonium hydroxide). The product fractions arecombined and concentrated, and the residue left under high vacuumovernight. The product is isolated as a pale yellow powder(0.50 g, 1.4mmol).

[1344]¹H-NMR (DMSO-d₆, 300 MHz) δ9.90 (br s, 2H); 8.35 (s, 1H); 8.16 (d,1H); 7.49 (d, 1H); 7.31 (dd, 1H); 7.22 (br d, 1H); 4.57 (d, 1H); 4.44(d, 1H); 4.20 (m, 1H); 3.18 (m, 2H); 2.23 (m, 1H); 1.80 (m, 1H); 1.39(s, 9H). ESI MS, [M+H]⁺=358.

[1345] F. 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride

[1346][1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester (1.70 g, 5.15 mmol) is dissolved in methanol (100 mL)and stirred at 0° C. while bubbling HCl_((g)) through the solution untilsaturated (became cloudy). The reaction mixture is left at roomtemperature for 10 minutes, then concentrated in vacuo. The residue iswashed with ethyl acetate and ether, and dried under high vacuum to givethe product as a pale yellow powder (1.33 g, 4 mmol).

[1347]¹H-NMR (DMSO-d₆, 300 MHz) δ8.81 (s, 1H); 8.73 (br s, 2H); 8.57 (d,1H); 7.87 (d, 1H); 7.65 (dd, 1H); 6.68 (br s, 2H); 4.73 (d, 1H); 4.60(d, 1H); 4.13 (m, 1H); 3.35 (m, 2H); 2.43 (m, 1H); 2.10 (m? 1H). ESI MS,[M+H]⁺=258.

[1348] G.1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chlorophenyl)urea trifluoroacetate

[1349] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (50mg, 0.15 mmol) and triethylamine (40mg, 0.40 mmol) indimethylformamide (3 mL) stirred at room temperature for 30 minutes, and4-chlorophenylisocyanate (25 mg, 0.16 mmol) added as a solution in DMF(2 mL). Left at room temperature for 1 hour, then removeddimethylformamide at 45° C./25 psi on air vortex blower. The residue isdissolved in 30% acetonitrile/water (2% trifluoroacetic acid) andpurified by preparative reverse phase HPLC with gradient elution 15-45%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsare combined, the acetonitrile removed in vacuo, and the aqueoussolution lyophilized to give the product as an off-white powder, whichis washed with acetonitrile (2 mL) to give pure product as a whitepowder (45 mg, 0.086 mmol).

[1350]¹H-NMR (DMSO-d₆, 300 MHz) δ9.60 (br s, 2H); 8.87 (s, 1H); 8.80 (s,1H); 8.37 (d, 1H); 7.62 (dd, 1H); 7.58 (d, 1H); 7.43 (d, 2H), 7.25 (d,2H); 6.65 (d, 1H); 4.64 (m, 2H); 4.36 (m, 1H); 3.28 (m, 2H); 2.40 (m,1H); 1.91 (m, 1H). ESI MS, [M+H]⁺=411.

EXAMPLE 102

[1351]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5-clorothiophen-2-yloxy)acetamidetrifluoroacetate

[1352] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (40 mg, 0.12 mmol) and diisopropylethylamine (130 mg, 1mmol) in dimethylformamide (1 mL) is stirred for 15 minutes at roomtemperature. The aforementioned solution is added to a solution of2-(5-chlorothiophen-2-yloxy)acetic acid (23 mg, 0.12 mmol),diisopropylethylamine (20 mg, 0.16 mmol) and2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) (39 mg, 0.12 mmol) in dimethylformamide (1 mL), which had beenstirring at room temperature for 5 minutes prior to addition. Thereaction mixture is left stirring at room temperature over the weekend.The dimethylformamide is removed at 45° C./25 psi on a vortex airblower, and the residue dissolved in 20% acetonitrile/water (2%trifluoroacetic acid) and purified by preparative reverse phase HPLCwith gradient elution 15-45% acetonitrile/water (0.1% trifluoroaceticacid). The product fractions are combined, the acetonitrile removed invacuo, and the aqueous solution lyophilized to give the product as anoff-white powder (34 mg, 0.062 mmol).

[1353]¹H-NMR (DMSO-d₆, 300 MHz) δ9.62 (br s, 2H); 8.80 (s, 1H); 8.64 (d,1H); 8.34 (d, 1H); 7.62 (dd, 111); 7.60 (d, 1H); 6.78 (d, 1H); 6.28 (d,1H); 4.59 (m, 5 H); 3.27 (m, 2H); 2.32 (m, 1H); 1.97 (m, 1H). ESI MS,[M+H]⁺=432.

EXAMPLE 103

[1354]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1355] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (40 mg, 0.12 mmol) and powdered potassium carbonate (80mg, 0.58 mmol) are dissolved/suspended in DMF (1 mL), and to thissolution is added 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole (41mg, 0. 12 mmol) as a solution in DMF (1 mL). The reaction mixture issonicated for 10 minutes, then stirred at room temperature overnight Thedimethylformamide is removed at 45° C./25 psi on a vortex air blower,and extracted the residue into methanol (2×10 mL). Diluted the filtratewith methanol (30 mL), and cooled at 0° C. whilst bubbling dry HCl_((g))through the solution until saturated. The reaction mixture is leftovernight at room temperature. The resulting red solution isconcentrated in vacuo and extracted into acetonitrile (2 mL), dilutedwith water (1% trifluoroacetic acid) and the insoluble solids filteredoff prior to purification of the crude material by reverse phasepreparative HPLC with gradient elution 20-60% acetonitrile/water (0.1%trifluoroacetic acid). The product fractions are combined, theacetonitrile removed in vacuo, and the aqueous solution lyophilized togive the product as an off-white powder (12 mg, 0.022 mmol).

[1356]¹H-NMR (DMSO-d₆, 300 MHz) δ11.43 (s, 1H); 9.61 (brs, 3H); 8.78 (s,1H); 8.36 (d, 1H); 7.67 (s, 1H); 7.63 (d, 1H); 7.59 (dd, 1H); 7.46 (d,1H); 7.13 (dd, 1H); 6.64 (d, 1H); 4.70 (d, 1H); 4.63 (d, 1H); 4.51 (m,2H); 4.19 (m, 1H); 3.34 (m, 2H); 2.45 (m, 1H); 2.07 (m, 1H). ESI MS,[M+H]⁺=421.

EXAMPLE 104

[1357]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate

[1358] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onehydrochloride (40 mg, 0.12 mmol) and diisopropylethylamine are dissolvedin DMF (1 mL) and added to 5-chlorothiophene-2-carboxylic acid azide (23mg, 0.12 mmol). The reaction mixture is heated at 100° C. for 20minutes, cooled to room temperature, and the dimethylformamide removedat 45° C./25 psi on a vortex air blower. The residue is dissolved in 30%acetonitrile/water (2% trifluoroacetic acid) and purified by preparativereverse phase HPLC with gradient elution 15-30% acetonitrile/water (0.1%trifluoroacetic acid). The fractions of the two different products areseparately combined, the acetonitrile removed in vacuo, and the aqueoussolutions lyophilized to give the products as white powders: urea (9 mg,0.017 mmol), amide (22 mg, 0.043 mmol).

[1359] Urea: ¹H-NMR (DMSO-d₆, 300 MHz) δ9.98 (s, 1H); 9.59 (br s, 2H);8.80 (s, 1H); 8.38 (d, 1H); 7.59 (m, 2H); 6.88 (d, 1H); 6.75 (d, 1H);6.24 (d, 1H); 4.67 (d, 1H); 4.59 (d, 1H); 4.39 (m, 1H); 3.27 (m, 2H);2.40 (m, 1H); 1.94 (m, 1H). ESI MS, [M+H]⁺=421.

[1360] Amide: ¹H-NMR (DMSO-d₆, 300 MHz) δ9.73 (br s, 2H); 9.02 (d, 1H);8.82 (s, 1H); 8.40 (d, 1H); 7.65 (m, 3H); 7.21 (d, 1H); 4.68 (m, 3H);3.31 (m, 2H); 2.37 (m, 1H); 2.06 (m, 1H). ESI MS, [M+H]⁺=421.

EXAMPLE 105

[1361]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amino}aceticacid methyl ester trifluoroacetate

[1362] A. 3-(S)-Amino 1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one

[1363] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride (600 mg, 1.82 mmol) is chromatographed on silica with 12%methanol/2% ammonium hydroxide (28% aqueous)/86% dichloromethane, andthe product fractions combined and concentrated to give the free base asa pale yellow powder (360 mg, 1.4 mmol).

[1364]¹H-NMR (DMSO-d₆, 300 MHz) δ8.35 (s, 1H); 8.16 (d. 1H); 7.74 (br s,2H); 7.47 (d, 1H); 7.29 (dd, 1H); 4.55 (d, 1H); 4.49 (d, 1H); 3.95 (brd, 2H); 3.55 (t, 1H); 3.J 8 (m, 2H); 2.27 (m, 1H); 1.69 (m, 1H). ESI MS,[M+H]⁺=258.

[1365] B.{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate

[1366] tert-Butyl bromoacetate (247 mg, 1.267 mmol) in dimethylformamide(5 mL) is added dropwise to a solution of3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one (326 mg,1.267 mmol) and pyridine (100 mg, 1.267 mmol) in dimethylformamide,stirring at room temperature. After 90 minutes an additional equivalentof pyridine (100 mg, 1.267 mmol) in dimethylformamide (2 mL) is added,followed by the dropwise addition of a second equivalent of tert-butylbromoacetate (247 mg, 1.267 mmol) in dimethylformamide (5 mL). Thereaction mixture is left at room temperature for 180 minutes, dilutedwith dichloromethane (150 mL) and flash chromatographed on silica withneat dichloromethane, then 20% methanol/5% ammonium hydroxide (28%aqueous)/75% dichloromethane. The crude product fractions are combinedand concentrated to give an impure yellow solid, which is dissolved in15% acetonitrile/water (2% trifluoroacetic acid) and purified bypreparative reverse phase HPLC with gradient elution 10-50%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsare combined and solvents removed in vacuo, and the residue left underhigh vacuum overnight. The product is isolated as a pale pink powder(300 mg, 0.808 mmol).

[1367]¹H-NMR (DMSO-d₆, 300 MHz) δ9.76 (br s, 3H); 8.82 (s, 1H); 8.39 (d,1H); 7.68 (d, 1H); 7.61 (dd, 1H); 4.64 (m, 2H); 4.11 (m, 3H); 3.33 (m,2H); 2.40 (m, 1H); 2.04 (m, 1H); 1.47 (s, 9H). ESI MS, [M+H]⁺=372.

[1368] C.{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amino}aceticacid methyl ester trifluoroacetate

[1369] Same coupling procedure as in EXAMPLE 102, except that thecoupling species are{[1-(4-aminoquinazolin-7-ylmethyl)-2oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate and3-(5-chlorothiophen-2-yl)acrylic acid. The residue from concentratingthe reaction mixture is dissolved in 40% acetonitrile/water (2%trifluoroacetic acid) and purified by preparative reverse phase HPLCwith gradient elution 30-100% acetonitrile/water (0.1% trifluoroaceticacid). The product fractions are combined and the solvents removed invacuo to give the tert-butyl ester intermediate as a white powder. Thisintermediate is dissolved in methanol, and cooled to 0° C. whilstbubbling dry HCl_((g)) through the solution until saturated. Thereaction mixture is left at room temperature overnight, thenconcentrated in vacuo, and the residue dissolved in 20%acetonitrile/water (2% trifluoroacetic acid) and purified by preparativereverse phase HPLC with gradient elution 10-100% acetonitrile/water(0.1% trifluoroacetic acid). The product fractions are combined, theacetonitrile removed in vacuo, and the aqueous solution lyophilized togive the product as a white powder (9 mg, 0.015 mmol).

[1370]¹H-NMR (DMSO-d₆, 300 MHz) rotamers observed: δ9.78 (br s, 2H);8.82, 8.83 (2s, 1H); 7.62 (m, 3H); 7.36 (m, 1H); 7.15 (m, 1H); 6.88,6.73(2d, 1H); 5.28, 4.17 (2t, 1H); 4.40 (m, 3H); 3.64, 3.59 (2s, 3H); 3.28(m, 2H); 2.37 (m, 1H); 2.10 (m, 1H). ESI MS, [M+H]⁺=500.

EXAMPLE 106

[1371] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1372] A. (2-Oxopyrrolidin-3-(R)-yl) carbamic acid tert-butyl ester

[1373] Same procedure as EXAMPLE 101A, but using the (R) enantiomerstarting material, instead of the (S).

[1374]¹H-NMR (CDCl₃, 300MHz) δ6.18 (m, 1H); 5.11 (m, 1H); 4.15 (m, 1H);3.35 (m, 2H); 2.70 (m, 1H); 1.96 (m, 1H); 1.45 (s, 9H). ESI MS,[M+H]⁺=201.

[1375] B. [1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(R)-yl]carbamicacid tert-butyl ester

[1376] Same procedure as EXAMPLE 101 D, but using the (R) enantiomer asstarting material, instead of the (S).

[1377]¹H-NMR (CDCl₃, 300 MHz) δ7.35 (d, 1H); 6.64 (d, 1H); 6.58 (dd,1H); 5.15 (br s, 1H); 4.40 (m, 4H); 4.19 (m, 1H); 3.24 (m, 2H); 2.60 (m,1H); 1.90 (m, 1H); 1.45 (s, 9H). ESI MS, [M+H]⁺=331.

[1378] C.[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]carbamic acidtert-butyl ester

[1379] Same procedure as EXAMPLE 101 E, but using the (R) enantiomer asstarting material, instead of the (S).

[1380]¹H-NMR (DMSO-d₆, 300 MHz) δ9.90 (br s, 2H); 8.35 (s, 1H); 8.16 (d,1H); 7.49 (d, 1H); 7.31 (dd, 1H); 7.22 (br d, 1H); 4.57 (d, 1H); 4.44(d, 1H); 4.20 (m, 1H); 3.18 (m, 2H); 2.23 (m, 1H); 1.80 (m, 1H); 1.39(s, 9H). ESI MS, [M+H]⁺=358.

[1381] D. 3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one

[1382] Same procedure as EXAMPLE 101 F, followed by procedure in EXAMPLE105A, but in each case using the (R) enantiomer as starting materialinstead of the (S).

[1383]¹H-NMR (DMSO-d₆, 300 MHz) δ8.81 (s, 1H); 8.73 (br s, 2H); 8.57 (d,1H); 7.87 (d, 1H); 7.65 (dd, if); 6.68 (br s, 2H); 4.73 (d, 1H); 4.60(d, 1H); 4.13 (m, 1H); 3.35 (m, 2H); 2.43 (m, 1H); 2.10 (m, 1H). ESI MS,[M+H]⁺=258.

[1384] E. 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1385] 3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one (36mg, 0.14 mmol) and 6-chlorothiophene-2-sulfonyl chloride (40 mg, 0.15mmol) are dissolved in dichloromethane (2 mL) and DMF (1 mL), andtriethylamine (36 mg, 0.35 mg) added. Left the reaction mixture stirringovernight at room temperature, before concentrating at 45° C./25 psi onair vortex blower. The residue is dissolved in 30% acetonitrile/water(2% trifluoroacetic acid) and purified by preparative reverse phase HPLCwith gradient elution 20-60% acetonitrile/water (0.1% trifluoroaceticacid). The product fractions are combined, the acetonitrile removed invacuo, and the aqueous solutions lyophilized to give the product as awhite powder (9 mg, 0.015 mmol).

[1386]¹H-NMR (DMSO-d₆, 300 MHz) δ9.61 (br s, 2H); 8.75 (m, 2H); 8.34 (d,1H); 8.27 (s, 1H); 8.05 (s, 1H); 8.02 (d, 1H); 7.55 (m, 3H); 4.55 (m,2H); 4.25 (m, 1H); 2.99 (m, 2H); 2.18 (m, 1H); 1.73 (m, 1H). ESI MS,[M+H]=488.

EXAMPLE 107

[1387] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1388] A.[1-(1-Chloroisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]carbamicacid tert-butyl ester

[1389] Same procedure as EXAMPLE 101D, but using(2-oxopyrrolidin-3-(R)-yl) carbamic acid tert-butyl ester (312 mg, 1.56mmol) and 7-bromomethyl-1-chloroisoquinoline (440 mg, 1.72 mmol) as thestarting materials. The crude product is purified by columnchromatography on silica with 50-100% ethyl acetate/hexanes. The productfractions are combined and concentrated to give the product as a paleyellow powder (471 mg, 1.25 mmol).

[1390]¹H-NMR (CDCl₃, 300 MHz) δ8.28 (d, 1H); 8.14 (s, 1H); 7.83 (d, 1H);7.67 (dd, I1H); 7.55 (d, 1H); 5.50 (br s, 1H); 4.77 (d, 1H); 4.65 (d,1H); 4.31 (m, 1H); 3.27 (m, 2H); 2.60 (m, 1H); 1.96 (m, 1H); 1.47 (s,9H). ESI MS, [M+H]⁺=376.

[1391] B. 3-(R)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)pyrrolidin-2-onetrifluoroacetate

[1392][1-(1-chloroisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]carbamicacid tert-butyl ester (384 mg, 1.02 mmol), phenol (962 mg, 10.2 mmol),and anhydrous ammonium acetate (1.576 g, 20.4 mmol) are combined in asealed tube, and heated at 100° C. overnight. Then the mixture iscooled, acetonitrile (20 mL) and water (20 mL) are added, and the phasesare separated. The aqueous phase is washed with ethyl acetate, andconcentrated to dryness. The residue from concentration is extractedinto methanol, filtered off solids, and the filtrate concentrated. Theresidue is dissolved in 10% acetonitrile/water (2% trifluoroacetic acid)and purified by preparative reverse phase HPLC with gradient elution10-30% acetonitrile/water (0.1% trifluoroacetic acid). The productfractions are combined, the solvents removed in vacuo, and the productdried under high vacuum. Isolated as a white powder (88 mg, 0.238 mmol).

[1393]¹H-NMR (DMSO-d₆, 300 MHz) δ9.11 (br s, 2H); 8.43 (br s, 2H); 8.37(s, 1H); 7.98 (d, 1H); 7.83 (dd, 1H); 7.69 (d, 1H); 7.24 (d, 1H); 4.66(d, 1H); 4.59 (d, 1H); 4.09 (m, 1H); 3.34 (m, 2H); 2.38 (m, 1H); 1.96(m, 1H). ESI MS, [M+H]⁺=257.

[1394] C. Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1395] 3-(R)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)pyrrolidin-2-onetrifluoroacetate (80 mg, 0.216 mmol) and diisopropylethylamine (140 mg,1.08 mmol) are dissolved in acetonitrile (12mL), and stirred at roomtemperature for 15 minutes before addingthieno[3,2-b]pyridine-2-sulfonyl chloride dropwise as a solution inacetonitrile (8 mL). The reaction mixture is left at room temperatureovernight, water (4 mL) added, and the solution concentrated in vacuo toremove the acetonitrile (ca. 4 mL of solution). 75% Acetonitrile/water(4 mL) is added, and the product purified by reverse phase preparativeHPLC with gradient elution 10-40% acetonitrile/water (0.1%trifluoroacetic acid). The product fractions are combined, theacetonitrile removed in vacuo, and the aqueous solution lyophilized togive the product as a white powder (52 mg, 0.092 mmol).

[1396]¹H-NMR (DMSO-d₆, 300 MHz) δ9.12 (br s, 2H); 8.86 (d, 1H); 8.77 (brd, 1H); 8.59 (d, 1H); 8.27 (s, 1H); 8.12 (s, 1H); 7.92 (d, 1H); 7.77(dd, 1H); 7.65 (d, 1H); 7.51 (dd, 1H); 7.21 (d, 1H); 4.61 (d, 1H); 4.47(d, 1H); 4.36 (m, 1H); 3.19 (m, 2H); 2.21 (m, 1H); 1.74 (m, 1H). ESI MS,[M+H]⁺=454.

EXAMPLE 108

[1397]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1398] A.[1-(4-chloroquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester

[1399] Same procedure as EXAMPLE 101D, but using7-bromomethyl4-chloroquinoline as the electrophile. The crude product ispurified by column chromatography on silica with 1-20% methanol/ethylacetate. The product fractions are combined and concentrated to give asemi-solid/oil which is triturated with ether to give the product as awhite powder.

[1400]¹H-NMR (DMSO-d₆, 300 MHz) δ8.83 (d, 1H); 8.17 (d, 1H); 7.95 (s,1H); 7.74 (d, 1H); 7.62 (dd, 1H); 7.22 (d, 1H); 4.66 (d, 1H); 4.57 (d,1H); 3.20 (m, 2H); 2.23 (m, 1H); 1.83 (m, 1H); 1.39 (s, 9H). ESI MS,[M+H]⁺=376.

[1401] B. 3-(S)-Amino-1-(4-aminoquinolin-7-ylmethyl)pyrrolidin-2-onehydrochloride

[1402][1-(4-chloroquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester (250 mg, 0.665 mmol), phenol (626 mg, 6.65 mmol), andanhydrous ammonium acetate (513 mg, 6.65 mmol) are combined and heatedat 100° C., with reflux apparatus, under nitrogen overnight. Then themixture is cooled to room temperature, and acetonitrile (2 mL) and water(2 mL) are added. The solution separates into 2 phases (both containingproduct), which are concentrated to dryness, and separately purified byreverse phase preparative HPLC with gradient elution 20-40%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsfrom each run are combined, the solvents are removed in vacuo, and theresidue dried under high vacuum overnight. The[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acidtert-butyl ester intermediate is dissolved in methanol, and cooled to 0°C., whilst bubbling dry HCl_((g)) through the solution until saturated.The reaction mixture is left at room temperature for 2 hours, andconcentrated in vacuo. The residue is washed with ether to give the pureproduct as a colorless powder (170 mg, 0.516 mmol).

[1403]¹H-NMR (DMSO-d₆, 300 MHz) δ9.15 (br s, 2H); 8.75 (br s, 2H); 8.50(d, 1H); 8.35 (d, 1H); 7.96 (s, 1H); 7.53 (d, 1H); 6.79 (d, 1H); 4.71(d, 1H); 4.58 (d, 1H); 4.11 (m, 1H); 3.11 (m, 2H); 2.45 (m, 1H); 2.13(m, 1H). ESI MS, [M+H]⁺=257.

[1404] C.1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1405] Same procedure as EXAMPLE 103, except with3-(S)-Amino-1-(4-aminoquinolin-7-ylmethyl)pyrrolidin-2-one hydrochlorideas starting material instead of3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride.

[1406]¹H-NMR (DMSO-d₆, 300 MHz) δ11.39 (s, 1H); 9.73 (br s, 1H); 8.97(br s, 2H); 8.38 (m, 1H); 7.73 (s, 1H); 7.62 (d, 1H); 7.52 (d, 1H); 7.45(d, 1H); 7.13 (dd, 1H); 6.75 (d, 1H); 6.64 (s, 1H); 4.65 (m, 2H); 4.54(d, 1H); 4.46 (d, 1H); 4.15 (m, 1H); 3.32 (m, 2H); 2.46 (m, 1H); 2.05(m, 1H). ESI MS, [M+H]⁺=420.

EXAMPLE 109

[1407]1(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylamino]pyrrolidin-2-onetrifluoroacetate

[1408] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onehydrochloride (40 mg, 0.12 mmol) and powdered potassium carbonate (80mg, 0.58 mmol) are dissolved/suspended in DMF (1 mL), and to thissolution is added 3-(5-chlorothiophen-2-yl)allyl bromide (30 mg, 0.126mmol) as a solution in DMF (1 mL). The reaction mixture is sonicated for10 minutes, then stirred at room temperature overnight. Thedimethylformamide is removed at 45° C./25 psi on a vortex air blower,the residue extracted into methanol (2×10 mL), and filtered off thesolids. The filtrate is concentrated, and the crude material is purifiedby reverse phase preparative HPLC with gradient elution 20-60%acetonitrilevater (0.1% trifluoroacetic acid). The product fractions arecombined, the acetonitrile removed in vacuo, and the aqueous solutionlyophilized to give the product as an off-white powder (15 mg, 0.028mmol).

[1409]¹H-NMR (DMSO-d₆, 300 MHz) δ9.64 (br s, 3H); 8.79 (s, H); 7.68 (d,H); 7.59 (dd, H); 7.08 (d, H); 6.95 (d, H); 5.96 (m, H); 4.71 (d, J);4.64 (d, H); 4.25 (t, H); 3.87 (d, H); 3.37 (m, 2H); 2.47 (m, H); 2.05(m, H). ESI MS, [M+H]⁺=414.

EXAMPLE 110

[1410]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate

[1411] Same procedure as EXAMPLE 102, but using3-(5-chlorothiophen-2-yl)acrylic acid instead of2-(5-chlorothiophen-2-yloxy)acetic acid.

[1412] ESI MS, [M+H]⁺=428.

EXAMPLE 111

[1413]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1414] Same procedure as EXAMPLE 103, but using a mixture of2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and2-chloromethyl-l-tert-butoxycarbonyl-6-chlorobenzimidazole instead of2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.

[1415] ESI MS, [M+H]⁺=422.

EXAMPLE 112

[1416]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-chlorothiophen-2-yl)ethenesulfonyl]amino}aceticacid methyl ester trifluoroacetate

[1417] Same initial procedure as EXAMPLE 106E, but using{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate instead of3-(R)-amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one, and2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride instead of6-chlorothiophene-2-sulfonyl chloride. The intermediate tert-butyl esteris isolated by reverse phase preparative HPLC with gradient elution10-100% acetonitrile/water (0.1% trifluoroacetic acid). The productfractions are combined, the solvents removed in vacuo, and theintermediate dried overnight under high vacuum. The dried material isdissolved in methanol, and cooled at 0° C. whilst bubbling HCl_((g))through the solution until saturated. Left stirring at room temperatureovernight. The reaction mixture is concentrated to dryness in vacuo, andthe residue dissolved in 20% acetonitrile/water (2% trifluoroaceticacid) and purified by preparative reverse phase HPLC with gradientelution 20-100% acetonitrile/water (0.1% trifluoroacetic acid). Theproduct fractions are combined, the acetonitrile removed in vacuo, andthe aqueous solution lyophilized to give the product as a white powder.

[1418] ESI MS, [M+H]⁺=536.

EXAMPLE 113

[1419]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate

[1420] Same procedure as EXAMPLE 103, but using{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate instead of3-(S)-amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onehydrochloride.

[1421] ESI MS, [M+H]⁺=493.

EXAMPLE 114

[1422]{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chlorothiophen-2-yl)allyl]amino}aceticacid methyl ester trifluoroacetate

[1423] Same procedure as EXAMPLE 103, but using{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate instead of3-(S)-amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onehydrochloride, and 3-(5-chlorothiophen-2-yl)allyl bromide instead ofadded 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.

[1424] ESI MS, [M+H]⁺=486.

EXAMPLE 115

[1425]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)ureido}aceticacid methyl ester trifluoroacetate

[1426] Same initial procedure as EXAMPLE 104, but using{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate instead of3-(R)-amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one. Only theurea is observed—no amide. The intermediate tert-butyl ester is isolatedby reverse phase preparative HPLC with gradient elution 10-100%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsare combined. the solvents removed in vacuo, and the intermediate driedovernight under high vacuum. The dried material is dissolved inmethanol, and cooled at 0° C. whilst bubbling HCl_((g)) through thesolution until saturated. Left stirring at room temperature overnight.The reaction mixture is concentrated to dryness in vacuo, and theresidue dissolved in 20% acetonitrile/water (2% trifluoroacetic acid)and purified by preparative reverse phase HPLC with gradient elution20-60% acetonitrile/water (0.1% trifluoroacetic acid). The productfractions are combined, the acetonitrile removed in vacuo, and theaqueous solution lyophilized to give the product as a white powder.

[1427] ESI MS, [M+H]⁺=489.

EXAMPLE 116

[1428]N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate

[1429] Same procedure as EXAMPLE 110, but using the (R) enantiomer asstarting material, instead of the (S).

[1430] ESI MS, [M+H]⁺=428.

EXAMPLE 117

[1431]1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1432] Same procedure as EXAMPLE 103, but using the (R) enantiomer asstarting material, instead of the (S).

[1433] ESI MS, [M+H]⁺=421.

EXAMPLE 118

[1434]1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1435] Same procedure as EXAMPLE 104, but using the (R) enantiomer asstarting material, instead of the (S).

[1436] Urea: ESI MS, [M+H]⁺=417. Amide: ESI MS, [M+H]⁺=402.

EXAMPLE 119

[1437]{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate

[1438] A.{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amino}aceticacid tert-butyl ester

[1439] Same initial procedure as EXAMPLE 105B, but using the (R)enantiomer as starting material, instead of the (S). No need to carryout the HPLC purification, because pure material is obtained by thecolumn chromatography. Product isolated as the free base.

[1440] ESI MS, [M+H]⁺=372.

[1441] B.{[1-(4-Aminoquinazolin-7-ylmethl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate

[1442] Same procedure as EXAMPLE 113, but using{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amino}aceticacid tert-butyl ester instead of{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}aceticacid tert-butyl ester trifluoroacetate as the starting material.

[1443] ESI MS, [M+H]⁺=493.

EXAMPLE 120

[1444]1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate

[1445] Same procedure as EXAMPLE 103, but using3-(S)-Amino-1-(4-aminoquinolin-7-ylmethyl)-pyrrolidin-2-onehydrochloride as starting material instead of3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onehydrochloride; and a mixture of2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and2-chloromethyl-1-tert-butoxycarbonyl-6-chlorobenzimidazole instead of2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.

[1446] ESI MS, [M+H]⁺=421.

[1447] The compounds of Examples 121-138 are synthesized using methodsand reagents analogous to those described herein.

EXAMPLE 121

[1448] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1449] ESI MS, [M+H]⁺=487, 489, Cl pattern.

EXAMPLE 122

[1450] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide

[1451] ESI MS, [M+H]⁺=470, 472, Cl pattern.

EXAMPLE 123

[1452] 7-Methoxy-naphthalene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1453] ESI MS, [M+H]⁺=477.

EXAMPLE 124

[1454] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1455] ESI MS, [M+H]⁺=464, 466, Cl pattern.

EXAMPLE 125

[1456] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1457] ESI MS, [M+H]⁺=488, 490, Cl pattern.

EXAMPLE 126

[1458] 5-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1459] ESI; MS, [M+H]⁺=493, 395, Cl pattern.

EXAMPLE 127

[1460] Thieno[3,2-b]pyridine-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1461] ESI MS, [M+H]⁺=460.

EXAMPLE 128

[1462] 6-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6ylmethyl)2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1463] ESI MS, [M+H]⁺=493, 495, Cl pattern.

EXAMPLE 129

[1464] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1465] ESI MS, [M+H]⁺=525, 527, Cl pattern.

EXAMPLE 130

[1466] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1467] ESI MS, [M+H]⁺=469, 471, Cl pattern.

EXAMPLE 131

[1468] 5-Chloro-benzo[b]thiophene-2-sulfonic acid[(S)1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1469] ESI MS, [M+H]⁺32 493, 495, Cl pattern.

EXAMPLE 132

[1470] 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1471] ESI MS, [M+H]⁺=493, 495, Cl pattern.

EXAMPLE 133

[1472] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1473] ESI MS, [M+H]⁺=525, 527, Cl pattern.

EXAMPLE 134

[1474] Thieno[3,2-b]pyridine-2-sulfonicacid[(S)1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1475] ESI MS, [M+H]⁺=460.

EXAMPLE 135

[1476] 6-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2.3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1477] ESI MS, [M+H]⁺=493, 495, Cl pattern.

EXAMPLE 136

[1478] 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1479] ESI MS, [M+H]⁺=525, 527, Cl pattern.

EXAMPLE 137

[1480] Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate

[1481] ESI MS, [M+H]⁺=460.

EXAMPLE 138

[1482] 6-Chloro-benzo[b]thiophene-2-sulfonic acid[(S)-1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide

[1483] ESI MS, [M+H]⁺=493, 495, Cl pattern.

EXAMPLE 139

[1484] 3-(R)-6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinoline-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate

[1485] 3-(R)-Amino-1-(4-aminoquinolin-7-ylmethyl)pyrrolidin-2-onebis-hydrochloride (160 mg, 0.48 mmol) and diisopropylethylamine (620 mg,4.8 mmol) are dissolved in actonitrile (2 mL); and6-chlorobenzo[b]thiophene-2-sulfonyl chloride (115 mg, 0.43 mmol) isthen added. The reaction mixture is stirred overnight at roomtemperature and then concentrated in vacuo. The residue is dissolved in30% acetonitrile/water (2% trifluoroacetic acid) and purified bypreparative reverse phase HPLC with gradient elution 20-60%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsare combined, the acetonitrile removed in vacuo, and the aqueoussolutions lyophilized to give the product as a white powder (46 mg,0.076 mmol).

[1486] ESI MS, [M+H+=487, 489, Cl pattern.

EXAMPLE 140

[1487] 2-(5-Chlorothiophen-2-yl)-ethenesulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate

[1488] 3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-onebis-trifluoroacetate (97 mg, 0.2 mmol) and diisopropylethylamine (260mg, 2 mmol) are dissolved in acetonitrile (8 mL), and2-(5-chlorothiophen-2-yl)ethenesulfonyl chloride (54 mg, 0.22 mmol) isthen added. The reaction mixture is stirred overnight at roomtemperature and then concentrated in vacuo. The residue is dissolved in30% acetonitrile/water (2% trifluoroacetic acid) and purified bypreparative reverse phase HPLC with gradient elution 10-100%acetonitrile/water (0.1% trifluoroacetic acid). The product fractionsare combined, the acetonitrile removed in vacuo, and the aqueoussolutions lyophilized to give the product as a white powder (32 mg,0.057 mmol). ESI MS, [M+H]⁺=464, 466, Cl pattern.

[1489] Similarly, the following compounds are synthesized using methodsand reagents analogous to those described above:

[1490] 3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-1H-indol-2-ylmethyl)amino]propionicacid methyl ester;

[1491]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(3-ethylbutyl)amino]pyrrolidin-2-one;

[1492]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-benzyl-(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[1493]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)thiazol-5-ylmethylamino]pyrrolidin-2-one;

[1494]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;

[1495]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-ylmethyl)amino]pyrrolidin-2-one;

[1496] 1(4-Aminoquinazolin-7-ylmethyl)-3-(S)-(6-chlorothieno[2,3-b]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[1497]1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;

[1498]3-{[1(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-ylamino]methyl}-1H-quinolin-2-one;

[1499]1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;

[1500] 2-(5-Chlorothiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(R)-yl]amide;

[1501]{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(R)-yl]amino}aceticacid isopropyl ester,

[1502]1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;and

[1503] 5-Chloro-1H-benzoimidazole-2-sulfonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide.

[1504] Reaction vessels are charged with4-hydroxy-2,3,5,6-tetraflurobenzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resin(0.20 g, 0.15 mmol). Each container is treated with methylene chloride(2 mL) for 10 minutes followed by an aromatic sulfonyl chloride (0.45mmol) and diisopropyethyl amine (0.104 ml, 0.60 mmol). The containersare sealed and agitated for about 16 h. The reaction mixtures areindividually filtered and sequentially washed with 20% aqueous DMF(10×), THF (5×) and dichloromethane (5×), then dried in vacuo at ambienttemperature overnight. By way of example6-chlorobenzothiophene-2-sulfonyl)oxy-2,3,5,6-tetrafluro-benzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resinshowed: ¹⁹F-NMR d-144.572, -145.608; IR (cm-1) 1684 (C═O stretch), 1391,(asymmetric SO₂ stretch) 1195, 1177 (symmetric SO₂ stretch).

[1505] Reaction vessels are charged witharylsulfonyloxy-2,3,5,6tetrafluro-benzamidomethyl-copoly-(styrene-1%divinylbenzene)-resins (0.024 g, 0.012 mmol), prepared as describedabove. The resins are swelled with DMF, then treated with a 0.01 Msolution of an amine (1 ml, 0.01 mmol) in DMF. The containers arecovered with aluminum foil and agitated for 72 h. The progress of thereaction is monitored by TLC; for sluggish reactions1,5,7-triazabicyclo[4.4.0]dec-5-ene resin is added. The reactionmixtures are individually filtered and the resins washed with methanol.The filtrates are concentrated with a stream of nitrogen. The residuesare redissolved in methanol and reconcentrated twice more. The resultingresidues are treated with 20% trifluoroacetic acid in methylene chloride(1 ml) and agitated overnight. The reaction mixture is concentrated by asteam of nitrogen. Methylene choride (1 ml) is added; concentrate with asteam of nitrogen. Methanol (1 ml) is added; concentrate with a streamof nitrogen. The final residues are analyzed by LC/mass spec; evidenceof desired product was obtained in each case. By way of example, theproduct from the reaction of6-chlorobenzothiophene-2-sulfonyl)oxy-2,3,5,6-tetrafluro-benzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resinwith2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid tert-butyl ester and subsequent deprotection with 20% TFA inmethylene chloride showed: M+H=461 . This material had an IC₅₀ againstFactor Xa of less than 500 nM.

[1506] By the methods described in this preparation2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carboxylicacid tert-butyl ester,2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester and2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[2,3-c]pyridine-1-carboxylicacid tert-butyl ester are reacted with fourteenarylsulfonyloxy-2,3,5,6-tetrafluro-benzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resinsto obtain, after deprotection, compounds encompassed by the followingformula:

[1507] wherein

[1508]  is selected from:

[1509] R₁ is H; and R₂ is selected from the group of formulae consistingof:

[1510]  or

[1511]  is selected from:

[1512] R₁ is H; and R₂ is selected from the group of formulae consistingof:

[1513]  or

[1514]  is selected from:

[1515] R₁ is H; and R₂ is selected from the group of formulae consistingof:

[1516] By the methods described herein compounds encompassed by thefollowing formula:

[1517] wherein

[1518]  is selected from:

[1519] R₁ is H; and R₂ is selected from the group of formulae consistingof:

[1520]  are also prepared.

[1521] By the methods described herein compounds encompassed by thefollowing formula:

[1522] wherein

[1523] R₁ is H; and R₂ is selected from the group of formulae consistingof:

[1524]  are also prepared.

[1525] The molecules described herein inhibit blood coagulation byvirtue of their ability to inhibit the penultimate enzyme in thecoagulation cascade, controlling the activity of Factor Xa. Both theactivity of free Factor Xa and Factor Xa assembled in the prothrombinasecomplex (Factor Xa, Factor Va, calcium and phospholipid) are inhibitedby compounds of formula I. The inhibition of the Factor Xa activity isobtained by direct complex formation between the inhibitor and theenzyme and is therefore independent of the plasma co-factor antithrombinIII. Effective inhibition of the Factor Xa activity is achieved byadministering the compounds either by oral administration, continuousintravenous infusion, bolus intravenous administration or any otherparenteral route such that it achieves the desired effect of preventingFactor Xa induced formation of thrombin from prothrombin.

[1526] Anticoagulant therapy is indicated for the treatment andprophylaxis of a variety of thrombotic conditions of both the venous andarterial vasculature. In the arterial system, abnormal thrombusformation is primarily associated with arteries of the coronary,cerebral and peripheral vasculature. The diseases associated withthrombotic occlusion of these vessels principally include acutemyocardial infarction (AMI), unstable angina, thromboembolism, acutevessel closure associated with thrombolytic therapy and percutaneoustransluminal coronary angioplasty (PTCA), transient ischemic attacks,stroke, intermittent claudication and bypass grafting (CABG) of thecoronary or peripheral arteries. Chronic anticoagulant therapy may alsobe beneficial in preventing the vessel luminal narrowing (restenosis)that often occurs following PTCA and CABG, and in the maintenance ofvascular access patency in long-term hemodialysis patients. With respectto the venous vasculature, pathologic thrombus formation frequentlyoccurs in the veins of the lower extremities following abdominal, kneeand hip surgery (deep vein thrombosis, DVT). DVT further predisposes thepatient to a higher risk of pulmonary thromboembolism. A systemic,disseminated intravascular coagulopathy (DIC) commonly occurs in bothvascular systems during septic shock, certain viral infections andcancer. This condition is characterized by a rapid consumption ofcoagulation factors and their plasma inhibitors resulting in theformation of life-threatening thrombin throughout the microvasculatureof several organ systems. The indications discussed above include some,but not all, of the possible clinical situations where anticoagulanttherapy is warranted. Those experienced in this field are well aware ofthe circumstances requiring either acute or chronic prophylacticanticoagulant therapy.

[1527] The compounds of this invention may be used alone or incombination with other diagnostic, cardioprotective, direct thrombininhibiting, anticoagulant, antiplatelet or fibrinolytic agents. Theseagents may include anti-coagulants such as warfarin or heparin;synthetic pentasaccharides; anti-platelet agents such as aspirin,piroxicam or ticlopidine; direct thrombin inhibitors, such asboroarginine derivatives, hirudin or argatroban (Novastan®); fibrinogenreceptor antagonists; statins/fibrates; or fibrinolytic agents(thrombolytic agents) such as tissue plasminogen activator, anistreplase(Eminase®), urokinase or streptokinase; or combinations thereof.

[1528] For example, adjunctive administration of inhibitors of theactivity of Factor Xa with standard heparin, low molecular weightheparin, direct thrombin inhibitors (i.e. hirudin), aspirin, fibrinogenreceptor antagonists, streptokinase, urokinase and/or tissue plasminogenactivator may result in greater antithrombotic or thrombolytic efficacyor efficiency. The compounds described herein may be administered totreat thrombotic complications in a variety of animals such as primates,including humans. Inhibition of factor Xa is useful not only in theanticoagulant therapy of individuals having thrombotic conditions but isuseful whenever inhibition of blood coagulation is required such as toprevent coagulation of stored whole blood and to prevent coagulation inother biological samples for testing or storage. Thus, any inhibitor ofFactor Xa activity can be added to or contacted with any mediumcontaining or suspected of containing Factor Xa and in which it isdesired that blood coagulation be inhibited.

[1529] The term cardioprotective agents as used herein, denotes agentsthat act to protect myocardium during ischemia. These cardioprotectiveagents include, but are nor limited to, adenosine agonists, β-blockersand Na/H exchange inhibitors. Adendosine agonists include thosecompounds disclosed in Spada et al., U.S. Pat. No. 5,364,862 and Spadaet al., U.S. Pat. No. 5,736,554, the disclosures of which are herebyincorporated herein by reference. An example of an adenosine agonists isAMP 579 (Rhone-Poulenc Rorer). An example of a Na/H exchange inhibitoris Cariporide (HOE 642).

[1530] The term anti-coagulant agents as used herein, denotes agentsthat inhibit blood coagulation. Such agents include warfarin (Coumadin®)and heparin.

[1531] The term anti-platelet agents as used herein, denotes agents thatinhibit platelet function such as by inhibiting the aggregation,adhesion or granular secretion of platelets. Such agents include thevarious known non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate,droxicam, diclofenac, sulfinpyrazone, and piroxicam (Feldane®),including pharmaceutically acceptable salts or prodrugs thereof. Othersuitable anti-platelet agents include ticlopidine (Ticlid),thromboxane-A2-receptor antagonists and thromboxane-A2-synthetaseinhibitors, as well as pharmaceutically acceptable salts or prodrugsthereof.

[1532] The phrase direct thrombin inhibitors (i.e. Factor IIainhibitors), as used herein, denotes inhibitors of the serine proteasethrombin. By inhibiting thrombin directly, the inhibition of thecleavage of fibrinogen to fibrin, activation of Factor XIIIa, activationof platelets, and feedback of thrombin to the coagulation cascade togenerate more thrombin, occurs. Such direct inhibitors includeboroarginine derivatives and boropeptides, hirudin and argatroban(Novastan®), including pharmaceutically acceptable salts and prodrugsthereof. Boroarginine derivatives and boropeptides include N-acetyl andpeptide derivatives of boronic acid, such as C-terminal β-aminoboronicacid derivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term hirudin, as usedherein, includes suitable derivatives or analogs of hirudin, referred toherein as hirulogs, such as disulfatohirudin.

[1533] The phrase fibrinolytic agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots.Such agents include tissue plasminogen activator, anistreplase(Eminase®), urokinase or streptokinase, including pharmaceuticallyacceptable salts or prodrugs thereof Tissue plasminogen activator (tPA)is commercially available from Genentech Inc., South San Francisco,Calif. The term urokinase, as used herein, is intended to denote bothdual and single chain urokinase, the latter also being referred toherein as prourokinase.

[1534] In addition to their use in anticoagulant therapy, inhibitors ofFactor Xa activity may find utility in the treatment or prevention ofother physiological conditions in which the generation of thrombin hasbeen implicated as playing a pathologic role. For example, thrombin hasbeen proposed to contribute to the morbidity and mortality of suchchronic and degenerative diseases as arthritis, cancer, atherosclerosis,restenosis post coronary angioplasty and Alzheimer's disease by virtueof its ability to regulate many different cell types through specificcleavage and activation of a cell surface thrombin receptor. Inhibitionof factor Xa activity will effectively block thrombin generation andtherefore neutralize any pathologic effects of thrombin on various celltypes.

[1535] According to a further feature of the invention there is provideda method for the treatment of a human or animal patient suffering from,or subject to, a physiological condition which can be ameliorated by theadministration of an inhibitor of the Factor Xa activity, for exampleconditions as hereinbefore described, which comprises the administrationto the patient of a therapeutically effective amount of compound offormula I or a composition containing a compound of formula I.“Effective amount” is meant to describe an amount of compound of thepresent invention effective in inhibiting the activity of Factor Xa andthus producing the desired therapeutic effect.

[1536] The present invention also includes within its scopepharmaceutical formulations which comprise at least one of the compoundsof formula I in association with a pharmaceutically acceptable carrieror coating.

[1537] The compounds utilized in combination therapy may be administeredsimultaneously, in either separate or combined formulations, or atdifferent times than the present compounds, e.g., sequentially, suchthat a combined effect is achieved. The amounts and regime ofadministration will be adjusted by the practitioner, by preferablyinitially lowering their standard doses and then titrating the resultsobtained.

[1538] In practice compounds of the present invention may generally beadministered parenterally, intravenously, subcutaneouslyintramuscularly, colonically, nasally, intraperitoneally, rectally ororally.

[1539] The products according to the invention may be presented in formspermitting administration by the most suitable route and the inventionalso relates to pharnmaceutical compositions containing at least oneproduct according to the invention which are suitable for use in humanor veterinary medicine. These compositions may be prepared according tothe customary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,suppositories powders, aqueous solutions or suspensions, injectablesolutions, elixirs or syrups, and can contain one or more agents chosenfrom the group comprising sweeteners, flavorings, colorings, orstabilizers in order to obtain pharmaceutically acceptable preparations.

[1540] The choice of vehicle and the content of active substance in thevehicle are generally determined in accordance with the solubility andchemical properties of the product, the particular mode ofadministration and the provisions to be observed in pharmaceuticalpractice. For example, excipients such as lactose, sodium citrate,calcium carbonate, dicalcium phosphate and disintegrating agents such asstarch, alginic acids and certain complex silicates combined withlubricants such as magnesium stearate, sodium lauryl sulfate and talcmay be used for preparing tablets. To prepare a capsule, it isadvantageous to use lactose and high molecular weight polyethyleneglycols. When aqueous suspensions are used they can contain emulsifyingagents or agents which facilitate suspension. Diluents such as sucrose,ethanol, polyethylene glycol, propylene glycol, glycerol and chloroformor mixtures thereof may also be used.

[1541] For parenteral administration, emulsions, suspensions orsolutions of the products according to the invention in vegetable oil,for example sesame oil, groundnut oil or olive oil, or aqueous-organicsolutions such as water and propylene glycol, injectable organic esterssuch as ethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilized by heating, irradiation ormicrofiltration.

[1542] Suitable compositions containing the compounds of the inventionmay be prepared by conventional means. For example, compounds of theinvention may be dissolved or suspended in a suitable carrier for use ina nebulizer or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

[1543] Solid compositions for rectal administration includesuppositories formulated in accordance with known methods and containingat least one compound of formula I.

[1544] The percentage of active ingredient in the compositions of theinvention may be varied, it being necessary that it should constitute aproportion such that a suitable dosage shall be obtained. Obviously,several unit dosage forms may be administered at about the same time.The dose employed will be determined by the physician, and depends uponthe desired therapeutic effect, the route of administration and theduration of the treatment, and the condition of the patient. In theadult, the doses are generally from about 0.01 to about 100, preferablyabout 0.01 to about 10, mg/kg body weight per day by inhalation, fromabout 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to10, mg/kg body weight per day by oral administration, and from about0.01 to about 50, preferably 0.01 to 10, mg/kg body weight per day byintravenous administration. In each particular case, the doses will bedetermined in accordance with the factors distinctive to the subject tobe treated, such as age, weight, general state of health and othercharacteristics which can influence the efficacy of the medicinalproduct.

[1545] The products according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

[1546] Compounds within the scope of the present invention exhibitmarked pharmacological activities according to tests described in theliterature which tests results are believed to correlate topharmacological activity in humans and other mammals. The followingpharmacological test results are typical characteristics of compounds ofthe present invention.

[1547] Enzyme Assays

[1548] The ability of the compounds in the present invention to act asinhibitors of factor Xa, thrombin, trypsin, tissue-plasminogen activator(t-PA), urokinase-plasminogen activator (u-PA), plasm in and activatedprotein C is evaluated by determining the concentration of inhibitorwhich resulted in a 50% loss in enzyme activity (IC₅₀) using purifiedenzymes.

[1549] All enzyme assays are carried out at room temperature in 96-wellmicrotiter plates using a final enzyme concentration of 1 nM. Theconcentrations of factor Xa and thrombin are determined by active sitetitration and the concentrations of all other enzymes are based on theprotein concentration supplied by the manufacturer. Compounds accordingto the invention are dissolved in DMSO, diluted with their respectivebuffers and assayed at a maximal final DMSO concentration of 1.25%.Compound dilutions are added to wells containing buffer and enzyme andpre-equilibrated for between 5 and 30 minutes. The enzyme reactions areinitiated by the addition of substrate and the color developed from thehydrolysis of the peptide-p-nitroanilide substrates is monitoredcontinuously for 5 minutes at 405 nm on a Vmax microplate reader(Molecular Devices). Under these conditions, less than 10% of thesubstrate is utilized in all assays. The initial velocities measured areused to calculate the amount of inhibitor which resulted in a 50%reduction of the control velocity (IC₅₀). The apparent Ki values arethen determined according to the Cheng-Prusoff equation (IC50Ki[1+[S]/Km]) assuming competitive inhibition kinetics.

[1550] By way of example, 7-methoxynaphthalene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate has a Ki value of 80 nM.

[1551] An additional in vitro assay may be used to evaluate the potencyof compounds according to the invention in normal human plasma. Theactivated partial thromboplastin time is a plasma-based clotting assaythat relies on the in situ generation of factor Xa, its assembly intothe prothrombinase complex and the subsequent generation of thrombin andfibrin which ultimately yields the formation of a clot as the assayendpoint. This assay is currently used clinically to monitor the ex vivoeffects of the commonly used anticoagulant drug heparin as well asdirect acting antithrombin agents undergoing clinical evaluation.Therefore, activity in this in vitro assay is considered as a surrogatemarker for in vivo anticoagulant activity.

[1552] Human Plasma Based Clotting Assay

[1553] Activated partial thromboplastin clotting times are determined induplicate on a MLA Electra 800 instrument. A volume of 100 ml ofcitrated normal human pooled plasma (George King Biomedical) is added toa cuvette containing 100 ml of a compound according to the invention inTris/NaCl buffer (pH 7.5) and placed in the instrument. Following a 3minute warming period the instrument automatically adds 100 ml ofactivated cephaloplastin reagent (Actin, Dade) followed by 100 ml of0.035 M CaCl₂ to initiate the clotting reaction. Clot formation isdetermined spectrophotometrically and measured in seconds. Compoundpotency is quantitated as the concentration required to double a controlclotting time measured with human plasma in the absence of the compoundaccording to the invention.

[1554] Compounds according to the invention may also be evaluated fortheir in vivo antithrombotic efficacy in two well established animalexperimental models of acute vascular thrombosis. A rabbit model ofjugular vein thrombosis and a rat model of carotid artery thrombosis areused to demonstrate the antithrombotic activity of these compounds indistinct animal model paradigms of human venous thrombosis and arterialthrombosis, respectively.

[1555] Experimental In Vivo Rabbit Venous Thrombosis Model

[1556] This is a well characterized model of fibrin rich venousthrombosis that is validated in the literature and shown to be sensitiveto several anticoagulant drugs including heparin (Antithrombotic Effectof Recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) inExperimental Venous Thrombosis—a Comparison with Low Molecular WeightHeparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, P. B.Ostergaard, J. G. L. Petersen, G. Nielsen and U. Hedner. Thrombosis andHaemostasis, 71, 214-219 (1994). The purpose of utilizing this model isto evaluate the ability of compounds to prevent the formation of venousthrombi (clots) in vivo generated at a site of injury and partial stasisin the jugular vein.

[1557] Male and female New Zealand white rabbits weighing 1.5-2 kg areanesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in a volumeof 1 ml/kg (i.m.). The right jugular vein is cannulated for infusion ofanesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a rate of approximately0.5 ml/hr) and administration of test substances. The right carotidartery is cannulated for recording arterial blood pressure andcollecting blood samples. Body temperature is maintained at 39 C with aGAYMAR T-PUMP. The left external jugular vein is isolated and all sidebranches along an exposed 2-3 cm of vessel are tied off. The internaljugular vein is cannulated, just above the bifurcation of the commonjugular, and the tip of the cannula is advanced just proximal to thecommon jugular vein. A 1 cm segment of the vein is isolated withnon-traumatic vascular clamps and a relative stenosis is formed by tyinga ligature around the vein with an 18G needle just below the distal mostclamp. This creates a region of reduced flow and partial stasis at theinjury site. The isolated segment is gently rinsed with saline 2-3 timesvia the cannula in the internal jugular. Thereafter the isolated segmentis filled with 0.5 ml of 0.5% polyoxyethylene ether (W-1) for 5 minutes.W-1 is a detergent which disrupts the endothelial cell lining of thesegment, thus providing a thrombogenic surface for initiating clotformation. After 5 minutes the W-1 is withdrawn from the segment, andthe segment is again gently rinsed with saline 2-3 times. The vascularclamps are then removed, restoring blood flow through this portion ofthe vessel. Clot formation is allowed to form and grow for 30 minutesafter which the vein is cut just below the stenotic ligature andinspected for blood flow (the absence of blood flow is recorded ascomplete occlusion). The entire isolated segment of vein is then ligatedand the formed clot is removed and weighed (wet weight). The effect oftest agents on final clot weights is used as the primary end point.Animals are maintained for an additional thirty minutes to obtain afinal pharmacodynamic measure of anticoagulation. Drug administration isinitiated 15 minutes prior to vascular injury with W-1 and continuedthrough the period of clot formation and maturation. Three blood samples(3 ml ea.) are obtained for evaluation of hemostatic parameters: onejust prior to administration of W-1; a second 30 minutes after removalof the vascular clamps and a third at the termination of the experiment.Antithrombotic efficacy is expressed as a reduction in the final clotweight in preparations treated with a compound according to theinvention relative to vehicle treated control animals.

[1558] Experimental In Vivo Rat Arterial Thrombosis Model

[1559] The antithrombotic efficacy of factor Xa inhibitors againstplatelet-rich arterial thrombosis may be evaluated using a wellcharacterized rat carotid artery FeCl₂-induced thrombosis model(Superior Activity of a Thromboxane Receptor Antagonist as Compared withAspirin in Rat Models of Arterial and Venous Thrombosis, W. A.Schumacher, C. L. Heran, T. E. Steinbacher, S. Youssef and M.L.Ogletree. Journal of Cardiovascular Pharmacology, 2, 526-533 (1993); RatModel of Arterial Thrombosis Induced by Ferric Chloride, K. D. Kurtz, B.W. Main, and G. E. Sandusky. Thrombosis Research, 60 269-280 (1990); TheEffect of Thrombin Inhibition in a Rat Arterial Thrombosis Model, R. J.Broersma, L. W. Kutcher and E. F. Heminger. Thrombosis Research 64405-412 (1991). This model is widely used to evaluate the antithromboticpotential of a variety of agents including heparin and the direct actingthrombin inhibitors.

[1560] Sprague Dawley rats weighing 375-450 g are anesthetized withsodium pentobarbital (50 mg/kg i.p.). Upon reaching an acceptable levelof anesthesia, the ventral surface of the neck is shaved and preparedfor aseptic surgery. Electrocardiogram electrodes are connected and leadII is monitored throughout the experiment. The right femoral vein andartery are cannulated with PE-50 tubing for administration of a compoundaccording to the invention and for obtaining blood samples andmonitoring blood pressure, respectively. A midline incision is made inthe-ventral surface of the neck. The trachea is exposed and intubatedwith PE-240 tubing to ensure airway patency. The right carotid artery isisolated and two 4-0 silk sutures are placed around the vessel tofacilitate instrumentation. An electromagnetic flow probe (0.95-1 mmlumen) is placed around the vessel to measure blood flow. Distal to theprobe a 4×4 mm strip of parafilm is placed under the vessel to isolateit from the surrounding muscle bed. After baseline flow measurements aremade, a 2×5 mm strip of filter paper previously saturated in 35% FeCl₂is placed on top of the vessel downstream from the probe for ten minutesand then removed. The FeCl₂ is thought to diffuse into the underlyingsegment of artery and cause deendothelialization resulting in acutethrombus formation. Following application of the FeCl₂-soaked filterpaper, blood pressure, carotid artery blood flow and heart rate aremonitored for an observation period of 60 minutes. Following occlusionof the vessel (defined as the attainment of zero blood flow), or 60minutes after filter paper application if patency is maintained, theartery is ligated proximal and distal to the area of injury and thevessel is excised. The thrombus is removed and weighed immediately andrecorded as the primary end point of the study.

[1561] Following surgical instrumentation a control blood sample (B1) isdrawn. All blood samples are collected from the arterial catheter andmixed with sodium citrate to prevent clotting. After each blood sample,the catheter is flushed with 0.5 ml of 0.9% saline. A compound accordingto the invention is administered intravenously (i.v.) starting 5 minutesprior to FeCl₂ application. The time between FeCl₂ application and thetime at which carotid blood flow reached zero is recorded as time toocclusion (TTO). For vessels that did not occlude within 60 minutes, TTOis assigned a value of 60 minutes. Five minutes after application ofFeCl₂, a second blood sample is drawn (B2). After 10 minutes of FeCl₂exposure, the filter paper is removed from the vessel and the animal ismonitored for the remainder of the experiment. Upon reaching zero bloodflow blood a third blood sample is drawn (B3) and the clot is removedand weighed. Template bleeding time measurements are performed on theforelimb toe pads at the same time that blood samples are obtained.Coagulation profiles consisting of activated partial thromboplastin time(APTT) and prothrombin time (PT) are performed on all blood samples. Insome instances a compound according to the invention may be administeredorally. Rats are restrained manually using standard techniques andcompounds are administered by intragastric gavage using a 18 gaugecurved dosing needle (volume of 5 ml/kg). Fifteen minutes afterintragastric dosing, the animal is anesthetized and instrumented asdescribed previously. Experiments are then performed according to theprotocol described above.

[1562] The present invention may be embodied in other specific formswithout departing from the spirit or essential attributes thereof.

What is claimed is:
 1.

wherein

 is a monocyclic heteroaryl group containing at least one nitrogen atom,or a bicyclic heteroaryl group which includes a first proximal ring thatis attached to Z and a ring distal to said first ring, said distal ringincluding at least one nitrogen atom; Z is alkylenyl,—(CH₂)_(r)C(O)NR″(CH₂)_(s)—, —(CH₂)_(s)R″NC(O)(CH₂)_(r)—,—(CH₂)_(r)NR″(CH₂)_(s)— or —(CH₂)_(s),NR″(CH₂)_(r)—; R₁ is hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aralkyl, optionally substituted heteroaralkyl,R′O(CH₂)_(x)—, R′O₂C(CH₂)_(x)—, R′C(O)(CH₂)_(x)—, Y¹Y²NC(O)CH₂)_(x)—, orY¹Y²(CH₂)_(x)—; R′ and R″ are independently hydrogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkenyl, optionally substitutedheteroaralkenyl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl; R₂ is hydrogen, optionally substitutedaralkyl, optionally substituted heteroaralkyl, optionally substitutedaralkenyl, optionally substituted heteroaralkenyl, R₃R₄NC(O)(CH₂)_(x)—,R₃S(O)_(p)— or R₃R₄NS(O)_(p)—; R₃ is hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted aralkyl, optionally substitutedheteroaralkyl, optionally substituted aralkenyl or optionallysubstituted heteroaralkenyl, or R₁ and R₃ taken together with the—N—S(O)_(p)—NR₄— moiety or the -N-S(O)p-NR₄- moiety through which R₁ andR₃ are linked form a 5 to 7 membered optionally substitutedheterocyclyl; and R₄ is hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl or optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aralkyl oroptionally substituted heteroaralkyl, or R₃ and R₄ taken together withthe nitrogen to which R₃ and R₄ are attached form an optionallysubstituted 4 to 7 membered heterocyclyl; X₁ and X_(1a) areindependently selected from H, optionally substituted alkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heteroaralkyl, or X₁ and X_(1a) takentogether form oxo; X₂ and X_(2a) are H, or taken together form oxo; X₃is H, hydroxy, optionally substituted alkyl, optionally substitutedaryl, optionally substituted heteroaryl, optionally substituted aralkylor optionally substituted heteroaralkyl, or X₃ and one of X₁ and X_(1a)taken together form a 4 to 7 membered cycloalkyl; X₄ is H, optionallysubstituted alkyl, optionally substituted aralkyl, or hydroxyalkyl; X₅,X_(5a) and X_(5b) are independently selected from H, R₅R₆N—,(hydroxy)HN—, (alkoxy)HN—, or (amino)HN—, R₇O—, R₅R₆NCO—, R₅R₆NSO₂—,R₇CO—, halo, cyano, nitro and R₈(O)C(CH₂)_(q)—, and when

 is a bicyclic heteroaryl group, one of X₅, X_(5a) and X_(5b) is asubstituent that is alpha to a nitrogen of said distal ring of

 and is selected from the group consisting of H, hydroxy and H₂N—,(optionally substituted lower alkyl)HN (hydroxy)HN—, (alkoxy)HN—, or(amino)HN—; Y¹ and Y₂ are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted aralkyl or optionally substituted heteroaralkyl,or Y¹ and Y₂ taken together with the N through which Y¹ and Y² arelinked form a 4 to 7 membered heterocyclyl; R₅ and R₆ are independentlyH or optionally substituted lower alkyl, or one of R₅ and R₆ is H andthe other of R₅ and R₆ is R₈(O)CCH₂— or lower acyl; R₇ is H, optionallysubstituted lower alkyl, lower acyl or R₈(O)CCH₂—; R₈ is H, optionallysubstituted lower alkyl, alkoxy or hydroxy; m is 0, 1, 2or 3; p and rare independently 1 or 2; q is 0 or 1, s is 0, 1 or 2; and x is 1, 2, 3,4, or 5, or a pharmaceutically acceptable salt thereof, an N-oxidethereof, a hydrate thereof or a solvate thereof.
 2.

wherein

 is a bicyclic heteroaryl which includes a first proximal ring that isattached to Z and a ring distal to said first ring, said distal ringincluding at least one nitrogen atom; Z is alkylenyl; R₁ is hydrogen,optionally substituted alkyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, R′O(CH₂)_(x)—, R′O₂C(CH₂)_(x)—,Y¹Y₂NC(O)(CH₂)_(x)—, or Y¹Y²N(CH₂)_(x)—; R′ is hydrogen, optionallysubstituted alkyl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl; R₂ is R₃S(O)_(p)— or R₃R₄NS(O)_(p)—; R₃ isoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted aralkyl,optionally substituted heteroaralkyl, optionally substituted aralkenylor optionally substituted heteroaralkenyl, or R₁ and R₃ taken togetherwith the —N—S(O)_(p)— moiety or the —N—S(O)_(p)—NR₄— moiety throughwhich R₁ and R₃ are linked form a 5 to 7 membered optionally substitutedheterocyclyl; and R₄ is optionally substituted alkyl, optionallysubstituted cycloalkyl or optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl, or R₃ and R₄ taken together with the nitrogento which R₃ and R₄ are attached form an optionally substituted 4 to 7membered heterocyclyl; X₁ and X_(1a) are independently selected from H,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl or optionallysubstituted heteroaralkyl, or X₁ and X_(1a) taken together form oxo; X₂and X_(2a) are H, or taken together form oxo; X₃ is H, hydroxy,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted aralkyl or optionallysubstituted heteroaralkyl, or X₃ and one of X₁ and X_(1a) taken togetherform a 4 to 7 membered cycloalkyl; X₄ is H, optionally substitutedalkyl, optionally substituted aralkyl, or hydroxyalkyl; X₅, X_(5a) andX5b are independently selected from H, R₅R₆N—, (hydroxy, alkoxy oramino)HN—, R₇O—, R₅R₆NCO—, R₅R₆NSO₂—, R₇CO—, halo, cyano, nitro orR₈(O)C(CH₂)_(q)—, and one of X₅, X_(5a), and X_(5b) is a substituentthat is alpha to a nitrogen of said distal ring of

 and is selected from the group consisting of H, hydroxy or H₂N—,(optionally substituted lower alkyl)HN (hydroxy)HN—, (alkoxy)HN—, or(amino)HN—; Y¹ and Y² are independently hydrogen, optionally substitutedalkyl, optionally substituted aryl, optionally substituted aralkyl oroptionally substituted heteroaralkyl, or Y₁ and Y² taken together withthe N through which Y¹ and Y² are linked form a 4 to 7 memberedheterocyclyl; R₅ and R₆ are independently H or optionally substitutedlower alkyl, or one of R₅ and R₆ is H and the other of R₅ and R₆ isR₈(O)CCH₂— or lower acyl; R₇ is H, optionally substituted lower alkyl,lower acyl or R₈(O)CCH₂—; R₈ is H, optionally substituted lower alkyl,alkoxy or hydroxy; m is 0, 1, 2or 3; p is 1 or 2; q is 0 or 1, and x is1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt thereof, anN-oxide thereof, a hydrate thereof or a solvate thereof.
 3. The compoundof claim 1 wherein

is a monocyclic heteroaryl group containing at least one nitrogen atom.4. The compound of claim 1 wherein Z is alkylenyl,—(CH₂)_(r)C(O)NR″(CH₂)_(s)—, —(CH₂)_(s)R″NC(O)(CH₂)_(r)—,—(CH₂)_(r)NR″(CH₂)_(s)— or —(CH₂)_(s)NR″(CH₂)_(r)—.
 5. The compound ofclaim 1 wherein R₁ is hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted aralkyl, optionallysubstituted heteroaralkyl, R′O(CH₂)_(x)—, R′O₂C(CH₂)_(x)—,R′(O)(CH₂)_(x)—, Y¹Y²NC(O)(CH₂)_(x)—, or Y¹Y²N(CH₂)_(x)—.
 6. Thecompound of claim 1 wherein R₂ is selected from the group consisting of


7. The compound of claim 1 wherein

is selected from the group consisting of


8. The compound of claim 1 wherein R₁ is H, optionally substitutedheteroaralkyl, optionally substituted aralkyl or optionally substitutedalkyl.
 9. The compound of claim 1 wherein R₂ is R₃S(O)_(p)—.
 10. Thecompound of claim 9 wherein p is
 2. 11. The compound of claim 9 whereinR₃ is optionally substituted phenyl, optionally substituted naphthyl,optionally substituted thienyl, optionally substituted benzothienyl,optionally substituted thienyopyridyl, optionally substitutedquinolinyl, or optionally substituted isoquinolinyl.
 12. The compound ofclaim 1 wherein Z is methylenyl and m is
 1. 13. The compound of claim 1wherein X₂ and X_(2a) taken together are oxo.
 14. The compound of claim1 wherein each of X₁, X_(1a), X₃ and X₄ is H.
 15. The compound of claim1 wherein

is optionally substituted isoquinolinyl.
 16. The compound of claim 15wherein Z is attached to isoquinolinyl at the 7-position thereof. 17.The compound of claim 1 wherein

is optionally substituted quinolinyl.
 18. The compound of claim 17wherein Z is attached to quinolinyl at the 7-position thereof.
 19. Thecompound of claim 1 wherein

is an optionally substituted quinazolinyl.
 20. The compound of claim 19wherein Z is attached to quinazolinyl at the 7-position thereof.
 21. Thecompound of claim 1 wherein

is an optionally substituted moiety of formula

and W is S, O or NR₁₁, wherein R₁₁ is H, alkyl, aralkyl, heteroaralkyl,R₈(O)C(CH₂)_(q)—, and A is CH or N.
 22. The compound of claim 21 whereinZ is bonded to said moiety through the 5 membered ring.
 23. The compoundof claim 1 wherein one of X₅, X_(5a) and X_(5b) is a substituent that ison the proximal ring of bicyclic

at a position that is alpha to where Z is attached to

and is selected from the group consisting of H, hydroxy and amino. 24.The compound of claim 23 wherein one of X₅, X_(5a), and X_(5b) ishydroxy or amino.
 25. The compound of claim 1 wherein one of X₅, X_(5a)and X_(5b) that substitutes the distal ring of

at the position alpha to a nitrogen thereof is H or (H, optionallysubstituted loweralkyl, hydroxy or amino)HN—.
 26. A compound accordingto claim 1 which is selected from3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-1H-indol-2-ylmethyl)amino]propionicacid methyl ester;1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(3-ethylbutyl)amino]pyrrolidin-2-one;1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[benzyl-(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)thiazol-5-ylmethylamino]pyrrolidin-2-one;1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-ylmethyl)amino]pyrrolidin-2-one;1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorothieno[2,3-b]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;3-{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-ylamino]methyl}-1H-quinolin-2-one;1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;2-(5-Chlorothiophen-2-yl)ethenesulfonicacid[2-oxo1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin3-(R)-yl]amide;{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(R)-yl]amino}aceticacid isopropyl ester;1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;5-Chloro-1H-benzoimidazole-2-sulfonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-yl]amidehydrochloride; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-hydroxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]amide;7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]methylamidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate; Benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl2-oxopyrrolidin-3-(S)-yl]amidehydrochloride; 7-Methoxynaphthalene-2-sulfonicacid[1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxo pyrrolidin-3-(S)-yl]amidetrifluoroacetate; 4-(2-Chloro-6-nitophenoxy)benzene sulfonicacid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; Benzo[b]thiophene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)yl]methylamide; 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide;7-Methoxynaphthalene-2-sulfonicacid[1-(2-aminoquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;7-Methoxynaphthalene-2-sulfonicacid[1-(2-hydroxyquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;7-Methoxynaphthalene-2-sulfonicacid[1-(1H-benzimidazol-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[2-(1H-benzimidazol-5-ylethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminoquinazolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[2-(6-aminothieno[2,3-d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(7-aminothieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(7-hydroxythieno[2,3-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate; 7-Methoxynaphthalene-2-sulfonicacid[1-(4-hydroxythieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate; Benzo[b]thiophene-2-sulfonicacid[1-(4-aminothieno[3,2-c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;Thieno[2,3-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;4-Pyridin-3-yl-thiophene-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;5′Chloro-[2,2′]bithiophenyl-5-sulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[2,3-d]pyrimidin-6yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; 5′-Chloro-[2,2′]bithiophenyl-5-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1,6-diamino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;3-(R)-5 Chlorothiophen-2-yl)-ethenesulphonicacid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 2-(S)-[[1-(4Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-chloro-benzo[b]thiophene-2-sulfonyl)-amino]-aceticacid methyl ester, trifluoroacetate;2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate; 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-quinolin-6-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide,ditrifluoroacetate:N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-acetamide;2-[3-(7-Methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-N-pyridin-4-yl-acetamide;6-Chlorobenzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate; 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;6-Chloro-thieno[2,3-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoacetate; Thieno[3,2-b]pyridine-2-sulfonicacid{2-oxo-1-[2-(pyridin-4ylamino)-ethyl]-pyrrolidin-3-yl}-amideditrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;(S)-5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate; (S)-6Chloro-benzo[b]thiophene-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester;((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic acidallyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;6-Chloro-benzo[b]thiophene-2-sulfonic acidmethyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;(S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amidetrifluoroacetate; (S)-Thieno[3,2-b]pyridine-2-sulfonicacid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amideditrifluoroacetate;([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid methyl ester;([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid isopropyl ester;([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid trifluoroacetate. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amidetrifluoroacetate;([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-aceticacid ethyl ester trifluoroacetate;3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-acrylamidetrifluoroacetate;1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chlorophenyl)ureatrifluoroacetate;N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5-chlorothiophen-2-yloxy)acetamidetrifluoroacetate;1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;1-[(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amidetrifluoroacetate;{[1-(4-Aminoquinazolin-7-ylmethyl2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amino}aceticacid methyl ester trifluoroacetate; 6-Chlorobenzo[b]thiophene-2-sulfonicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-aminoisoquinolin -7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylamino]pyrrolidin-2-onetrifluoroacetate;N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate; 1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-one trifluoroacetafe;{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-chlorothiophen-2-yl)ethenesulfonyl]amino}aceticacid methyl ester trifluoroacetate;{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][(5-chlorothiophen-2-yl)allyl]amino}aceticacid methyl ester trifluoroacetate;{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)ureido}aceticacid methyl ester trifluoroacetate;N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)acrylamidetrifluoroacetate;1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate;1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylicacid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate;{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]aceticacid methyl ester trifluoroacetate;1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)-yl]-amide;7-Methoxy-naphthalene-2-sulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic acid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate. 5′-Chloro-[2,2′]bithiophenyl-5-sulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 5′-Chloro[2,2′]bithiophenyl-5-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[(S)-1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[(S)1-(4-amino-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; 5′-Chloro-[2,2′]bithiophenyl-5-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; Chloro-benzo[b]thiophene-2-sulfonicacid[(S)-1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide;6-Chloro-benzo[b]thiophene-2-sulfonic acid[1- (4-aminoquinolin-7-ylmethyl)-2-oxo-3(R)-pyrrolidin-3-yl]amide trifluoroacetate; and2-(5-Chlorothiophen-2-yl)-ethenesulfonic acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate.
 27. A compoundaccording to claim 1 which is selected from7-Methoxynaphthalene-2-sulfonicacid[1-(6methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amidetrifluoroacetate;1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-onetrifluoroacetate: 2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;2-(5-Chloro-thiophen-2-yl)-ethenesulfonicacid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amidetrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic acid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amidetrifluoroacetate: 6-Chlorobenzo[b]thiophene-2-sulfonicacid{2-oxo-1-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate;((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-aceticacid methyl ester; Thieno[3,2-b]pyridine-2-sulfonicacid[2-oxo-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amideditrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonicacid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 2(S)-(5Chloro-thiophen2-yl)-ethenesulfonicacid[1-(4amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amidetrifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonicacid[1-(1,6diamino-isoquinolin-7ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide bistrifluoroacetate;6-Chlorobenzo[b]thiophene-2-sulfonic acid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-3(R)-pyrrolidin-3-yl]amide trifluoroacetate; and2-(5-Chlorothiophen-2-yl)-ethenesulfonic acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate.
 28. A compoundaccording to claim 1 of the formula

wherein

 is a radical selected from the group consisting of

W is S, O or NR₁₁, wherein R₁₁ is H, alkyl, aralkyl, heteroaralkyl orR₈(O)C(CH₂)_(q)—; A is CH or N; and R₂ is a radical selected from thegroup consisting of


29. A compound according to claim 1 of the formula

wherein

R₁ is H; and R₂ is a radical selected from the group consisting of:

R₁ is H; and R₂ is a radical selected from the group consisting of:

R₁ is H; and R₂ a radical selected from the group consisting of:

R₁ is H; and R₂ is a radical selected from the group consisting of:


30. A pharmaceutical composition comprising a pharmaceuticallyacceptable amount of a compound according to claim 1 and apharmaceutically acceptable carrier.
 31. A method for treating a patientsuffering from a physiological disorder capable of being modulated byinhibiting an activity of Factor Xa comprising administering to thepatient a therapeutically effective amount of a compound according toclaim
 1. 32. The method according to claim 31 wherein the physiologicaldisorder is abnormal thrombus formation, acute myocardial infarction,unstable angina, thromboembolism, acute vessel closure associated withthrombolytic therapy or percutaneous transluminal coronary angioplasty,transient ischemic attacks, stroke, pathologic thrombus formationoccurring in the veins of the lower extremities following abdominal,knee and hip surgery, a risk of pulmonary thromboembolism, ordisseminated systemic intravascular coagulopathy occurring in vascularsystems during septic shock, certain viral infections or cancer.
 33. Themethod according to claim 31 wherein the physiological disorder isabnormal thrombus formation, acute myocardial infarction, unstableangina, thromboembolism, acute vessel closure associated withthrombolytic therapy, transient ischemic attacks, restenosis postcoronary or venous angioplasty, pathologic thrombus formation occurringin the veins of the lower extremities following abdominal, knee and hipsurgery or a risk of pulmonary thromboembolism.
 34. The method accordingto claim 31 wherein the physiological disorder is stroke, vessel luminalnarrowing, or disseminated systemic intravascular coagulopathy occurringin vascular systems during septic shock, certain viral infections orcancer.
 35. The method of claim 31 wherein said compound according toclaim 1 is administered in combination with at least one other agentselected from diagnostic agents, cardioprotective agents, directthrombin inhibiting agents, anticoagulant agents, antiplatelet agentsand fibrinoloytic agents.
 36. The method of claim 35 wherein said otheragent is selected from standard heparin, low molecular weight heparin,direct thrombin inhibitors, aspirin, fibrinogen receptor antagonists,streptokinase, urokinase and tissue plasminogen activator.
 37. Themethod of claim 36 wherein said other agent is selected from directthrombin inhibitors and fibrinogen receptor antagonists.
 38. The methodof claim 37 wherein said thrombin inhibitor is selected fromboroarginine derivatives, boropeptides, hirudin, argatroban and thepharmaceutically acceptable salts, prodrugs, derivatives and analogsthereof.
 39. The pharmaceutical composition of claim 30 furthercomprising at least one other agent selected from diagnostic agents,cardioprotective agents, direct thrombin inhibiting agents,anticoagulant agents, antiplatelet agents and fibrinoloytic agents. 40.The pharmaceutical composition of claim 39 wherein said other agent isselected from standard heparin, low molecular weight heparin, directthrombin inhibitors, aspirin, fibrinogen receptor antagonists,streptokinase, urokinase and tissue plasminogen activator.
 41. Thepharmaceutical composition of claim 40 wherein said other agent isselected from direct thrombin inhibitors and fibrinogen receptorantagonists.
 42. A kit for treating a patient suffering from aphysiological disorder capable of being modulated by inhibiting anactivity of Factor Xa, said kit comprising a plurality of separatecontainers, wherein at least one of said containers contains a compoundaccording to claim 1 and at least one other of said containers containsat least one other agent selected from diagnostic agents,cardioprotective agents, direct thrombin inhibiting agents,anticoagulant agents, antiplatelet agents and fibrinoloytic agents, eachof said containers optionally further containing a pharmaceuticallyacceptable carrier.